Tricyclic compounds, preparation method and pharmaceutical compositions containing same

ABSTRACT

The invention concerns compounds of formula (I) in which: A forms a tricyclic system of formula A 1 , A 2 , A 3  or A 4 ; R 1  represents a hydrogen atom, an alkyl, hydroxy, alkoxy or oxo group; (R 2 ) m  and (R 3 ) m′  are such as defined in the description; n represents an integer such that 0≦n≦3; p represents an integer such as defined in the description; B represents a group (a) or (b). The invention is useful for preparing medicines.

The prsent application is a U.S. National Application filed under 35 USC371 of PCT/FR98/02694 filed Dec. 11, 1998, based upon French applicationSerial No. 98.00424 filed Jan. 16, 1998.

FIELD OF THE INVENTION

The present invention relates to new tricyclic compounds.

DESCRIPTION OF THE PRIOR ART

There are known from the prior art 2,3-dihydrophenalene compounds (J.Chem. Soc. C, 1971, 9, pp1607-1609) which are described as synthesisintermediates, and 1,3,4,5-tetrahydrobenzo[cd]indole compounds (EP 353557) for use in the preparation of platelet aggregation inhibitors.

Moreover, Application EP 737 670 describes tricyclic amide compounds asmelatoninergic receptor ligands.

BACKGROUND OF THE INVENTION

Numerous studies in the last ten years have demonstrated the key role ofmelatonin (N-acetyl-5-methoxytryptamine) in many physiopathologicalphenomena and in the control of the circadian rhythm. Its half-life isquite short, however, owing to the fact that it is rapidly metabolised.Great interest therefore lies in the possibility of providing theclinician with melatonin analogues that are metabolically more stable,have an agonist or antagonist character and may be expected to have atherapeutic effect that is superior to that of the hormone itself.

In addition to their beneficial action on circadian rhythm disorders (J.Neurosurg. 1985, 63, pp 321-341) and sleep disorders(Psychopharmacology, 1990, 100, pp 222-226), ligands of themelatoninergic system have valuable pharmacological properties inrespect of the central nervous system, especially anxiolytic andantipsychotic properties (Neuropharmacology of Pineal Secretions, 1990,8 (3-4), pp 264-272) and analgesic properties (Pharmacopsychiat., 1987,20, pp 222-223) as well as for the treatment of Parkinson's disease (J.Neurosurg. 1985, 63, pp 321-341) and Alzheimer's disease (BrainResearch, 1990, 528. pp 170-174). Those compounds have also demonstratedactivity in respect of certain cancers (Melatonin—Clinical Perspectives,Oxford University Press, 1988, pp 164-165), ovulation (Science 1987,227, pp 714-720), diabetes (Clinical Endocrinology, 1986, 24, pp359-364), and in the treatment of obesity (International Journal ofEating Disorders, 1996, 20 (4), pp 443-446).

Those various effects are exerted via the intermediary of specificmelatonin receptors. Molecular biology studies have demonstrated theexistence of a number of receptor sub-types that are capable of bindingthat hormone (Trends Pharmacol. Sci., 1995, 16, p. 50; WO 97.04094). Ithas been possible for various species, including mammals, for some ofthose receptors to be located and characterised. In order to be able tounderstand the physiological functions of those receptors better, it isof great advantage to have available specific ligands. Moreover, suchcompounds, by interacting selectively with one or other of thosereceptors, may be excellent medicaments for the clinician in thetreatment of pathologies associated with the melatoninergic system, someof which have been mentioned above.

The compounds of the present invention are new and have very strongaffinity for melatonin receptors and/or selectivity for one or other ofthe melatoninergic receptor sub-types.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates more especially to compounds of formula(I)

wherein:

A forms with the group to which it is bonded a tricyclic system selectedfrom A₁, A₂, A₃ and A₄:

R¹ represents a hydrogen atom, a halogen atom or a linear or branched(C₁-C₆)alkyl, linear or branched (C₁-C₆)alkoxy, hydroxy or oxo group,

R² and R³, which may be the same or different, represent a halogen atomor an R_(a), OR_(a), COR_(a), OCOR_(a) or COOR_(a) group (wherein R_(a)represents a hydrogen atom, an optionally substituted linear or branched(C₁-C₆)alkyl group, linear or branched (C₁-C₆)trihaloalkyl, anoptionally substituted linear or branched (C₂-C₆)alkenyl group, anoptionally substituted linear or branched (C₂-C₆)alkynyl group, anoptionally substituted (C₃-C₈)cycloalkyl group, an optionallysubstituted (C₃-C₈)cycloalkyl-(C₁-C₆)alkyl group in which the alkylmoiety is linear or branched, or an optionally substituted aryl group),

the symbols (R²)_(m) and (R³)_(m′) denote that the ring in question maybe substituted by from 1 to 3 groups (which may be the same ordifferent) belonging to the definitions for R² and R³,

X, when A represents a tricyclic system A₁, A₂, A₃ or A₄, represents asulphur atom, a (CH₂)_(q) group (wherein q is 1 or 2), a —CH═CH— group,or an NR⁴ group (wherein R⁴ represents a hydrogen atom or an optionallysubstituted linear or branched (C₁-C₆)alkyl group),

 or X represents an oxygen atom when A represents the tricyclic systemA₁,

n is an integer such that 0≦n≦3

p is an integer such that 1≦p≦3 when n is 1, 2 or 3 and the

 chain is in the b position and A represents either a group A₂, A₃ or A₄wherein X represents a —CH═CH— group, or a group A₁,

 and such that 0≦p≦3 in all other cases,

 it being possible for the

 chain to be unsubstituted or substituted by one or more groups, whichmay be the same or different, selected from R_(a), OR_(a), COR_(a),COOR_(a) or halogen atoms,

B represents:

an

 group wherein R_(a) is as defined hereinbefore, Z represents an oxygenatom or a sulphur atom, and R⁵ represents an R_(a) group or an NR⁶R⁷group wherein R⁶ and R⁷, which may be the same or different, representan R_(a) group,

or a

 group wherein Z, R⁶ and R⁷ are as defined hereinbefore,

the symbol denotes that the bond may be single or double provided thatthe valency of the atoms is respected,

 it being understood that the symbol

 is used to denote the formula

 (in which case p is other than 0),

 with the proviso that:

when the tricyclic group of formula A₁ is a6-methoxytetrahydrobenzo[cd]indole, B cannot represent an NHCOMe group,

the compound of formula (I) cannot representN-(4-methyl-2,3-dihydro-1H-1-phenalenyl)-1-cyclopropanecarboxamide,N-(4-methyl-2,3-dihydro-1H-1-phenalenyl)-2-chloroacetamide,2-methyl-1,3,4,5-tetrahydrobenzo[cd]indole-3-carboxamide,N-(5-hydroxy-1,2,2a,3,4,5-hexahydro-4-acenaphthylenyl)acetamide,N-(5-hydroxy-1,2,2a,3,4,5-hexahydro-4-acenaphthylenyl)benzamide orN-(1,2,2a,3,4,5-hexahydro-4-acenaphthylenyl)acetamide,

 it being understood that:

“aryl” is used to denote a phenyl or naphthyl group each optionallysubstituted by one or more groups, which may be the same or different,selected from hydroxy, linear or branched (C₁-C₆)-alkoxy, linear orbranched (C₁-C₆)alkyl, cyano, nitro, amino, trihaloalkyl, or halogenatoms,

the expression “optionally substituted” applied to the terms “alkyl”,“alkenyl” and “alkynyl” denotes that those groups may be substituted byone or more groups, which may be the same or different, selected fromhydroxy, linear or branched (C₁-C₆)alkoxy, aryl, or halogen atoms,

the expression “optionally substituted” applied to the terms“cycloalkyl” and “cycloalkylalkyl” denotes that the cyclic moiety may besubstituted by one or more groups selected from hydroxy, linear orbranched (C₁-C₆)alkoxy, oxo, or halogen atoms,

their enantiomers and diastereoisomers, and addition salts thereof witha pharmaceutically acceptable acid or base.

Amongst the pharmaceutically acceptable acids there may be mentioned byway of non-limiting example hydrochloric acid, hydrobromic acid,sulphuric acid, phosphonic acid, acetic acid, trifluoroacetic acid,lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid,fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid,methanesulphonic acid, camphoric acid, oxalic acid, etc.

Amongst the pharmaceutically acceptable bases there may be mentioned byway of non-limiting example sodium hydroxide, potassium hydroxide,triethylamine, tert-butylamine, etc.

An advantageous embodiment of the present invention relates to compoundsof formula (I) represented by formula (I_(A)):

wherein:

A forms with the group to which it is bonded a tricyclic system selectedfrom A′₁, A′₂, A′₃ and A′₄:

R¹ represents a hydrogen atom, a halogen atom or a linear or branched(C₁-C₆)alkyl, linear or branched (C₁-C₆)alkoxy, hydroxy or oxo group,

R² and R³, which may be the same or different, represent a halogen atomor an R_(a), OR_(a), COR_(a), OCOR_(a) or COOR_(a) group (wherein R_(a)represents a hydrogen atom, an optionally substituted linear or branched(C₁-C₆)alkyl group, linear or branched (C₁-C₆)trihaloalkyl, anoptionally substituted linear or branched (C₂-C₆)alkenyl group, anoptionally substituted linear or branched (C₂-C₆)alkynyl group, anoptionally substituted (C₃-C₈)cycloalkyl group, an optionallysubstituted (C₃-C₈)cycloalkyl-(C₁-C₆)alkyl group in which the alkylmoiety is linear or branched, or an optionally substituted aryl group),

the symbols (R²)_(m) and (R³)_(m′) denote that the ring in question maybe substituted by from 1 to 3 groups (which may be the same ordifferent) belonging to the definitions for R² and R³,

X, when A represents a tricyclic system A′₁, A′₂, A′₃ or A′₄, representsa sulphur atom, a (CH₂)_(q) group (wherein q is 1 or 2), a —CH═CH—group, or an NR⁴ group (wherein R⁴ represents a hydrogen atom or anoptionally substituted linear or branched (C₁-C₆)alkyl group),

 or X represents an oxygen atom when A represents the tricyclic systemA′₁,

n is an integer such that 0≦n≦3

p is an integer such that 1≦p≦3 when n is 1, 2 or 3 and the —(CH₂)_(p)—Bchain is in the b 20 position and A represents either a group A′₂, A′₃or A′₄ wherein X represents a —CH═CH— group, or a group A′₁,

 and such that 0≦p≦3 in all other cases,

it being possible for the (CH₂)_(p) chain to be unsubstituted orsubstituted by one or more groups, which may be the same or different,selected from R_(a), OR_(a), COR_(a), COOR_(a) or halogen atoms,

B represents:

an

 group wherein R_(a) is as defined hereinbefore, Z represents an oxygenatom or a sulphur atom, and R⁵ represents an R_(a) group or an NR⁶R⁷group wherein R⁶ and R⁷, which may be the same or different, representan R_(a) group,

or a

 group wherein Z, R⁶ and R⁷ are as defined hereinbefore,

the symbol denotes that the bond may be single or double provided thatthe valency of the atoms is respected,

 with the proviso that:

when the tricyclic group of formula A′₁ is a6-methoxytetrahydrobenzo[cd]indole, B cannot represent an NHCOMe group,

the compound of formula (I) cannot representN-(4-methyl-2,3-dihydro-1H-1-phenalenyl)-1-cyclopropanecarboxamide,N-(4-methyl-2,3-dihydro-1H-1-phenalenyl)-2-chloroacetamide,2-methyl-1,3,4,5-tetrahydrobenzo[cd]indole-3-carboxamide,N-(5-hydroxy-1,2,2a,3,4,5-hexahydro-4-acenaphthylenyl)acetamide,N-(5-hydroxy-1,2,2a,3,4,5-hexahydro-4-acenaphthylenyl)benzamide orN-(1,2,2a,3,4,5-hexahydro-4-acenaphthylenyl)acetamide,

 it being understood that:

“aryl” is used to denote a phenyl or naphthyl group each optionallysubstituted by one or more groups, which may be the same or different,selected from hydroxy, linear or branched (C₁-C₆)alkoxy, linear orbranched (C₁-C₆)alkyl, cyano, nitro, amino, trihaloalkyl, or halogenatoms,

the expression “optionally substituted” applied to the terms “alkyl”,“alkenyl” and “alkynyl” denotes that those groups may be substituted byone or more groups, which may be the same or different, selected fromhydroxy, linear or branched (C₁-C₆)alkoxy, aryl, or halogen atoms,

the expression “optionally substituted” applied to the terms“cycloalkyl” and “cycloalkylalkyl” denotes that the cyclic moiety may besubstituted by one or more groups, which may be the same or different,selected from hydroxy, linear or branched (C₁-C₆)alkoxy, oxo, or halogenatoms,

their enantiomers and diastereoisomers, and addition salts thereof witha pharmaceutically acceptable acid or base.

A further advantageous embodiment of the present invention relates tocompounds of formula (I) represented by formula (I_(B)):

wherein

A forms with the group to which it is bonded a tricyclic system selectedfrom A″₁, A″₂, A″₃ and A″₄:

R¹ represents a hydrogen atom, a halogen atom or a linear or branched(C₁-C₆)alkyl, linear or branched (C₁-C₆)alkoxy, hydroxy or oxo group,

R² and R³, which may be the same or different, represent a halogen atomor an R_(a), OR_(a). COR_(a), OCOR_(a) or COOR_(a) group (wherein R_(a)represents a hydrogen atom, an optionally substituted linear or branched(C₁-C₆)alkyl group, linear or branched (C₁-C₆)trihaloalkyl, anoptionally substituted linear or branched (C₂-C₆)alkenyl group, anoptionally substituted linear or branched (C₂-C₆)alkynyl group, anoptionally substituted (C₃-C₈)cycloalkyl group, an optionallysubstituted (C₃-C₈)cycloalkyl-(C₁-C₆)alkyl group in which the alkylmoiety is linear or branched, or an optionally substituted aryl group),

the symbols (R²)_(m) and (R³)_(m′) denote that the ring in question maybe substituted by from 1 to 3 groups (which may be the same ordifferent) belonging to the definitions for R² and R³,

X, when A represents a tricyclic system A″₁, A″₂, A″₃ or A″₄, representsa sulphur atom, a (CH₂)_(q) group (wherein q is 1 or 2), a —CH═CH—group, or an NR⁴ group (wherein R⁴ represents a hydrogen atom or anoptionally substituted linear or branched (C₁-C₆)-alkyl group), or Xrepresents an oxygen atom when A represents the tricyclic system A″₁,

n is an integer such that 0≦n≦3

p is an integer such that 1≦p≦3

it being possible for the

 chain to be unsubstituted or substituted by one or more groups, whichmay be the same or different, selected from R_(a), OR_(a), COR_(a),COOR_(a) or halogen atoms,

B represents:

an

 group wherein R_(a) is as defined hereinbefore, Z represents an oxygenatom or a sulphur atom, and R⁵ represents an R_(a) group or an NR⁶R⁷group wherein R⁶ and R⁷, which may be the same or different, representan R_(a) group,

or a

 group wherein Z, R⁶ and R⁷ are as defined hereinbefore,

the symbol denotes that the bond may be single or double provided thatthe valency of the atoms is respected,

 it being understood that:

“aryl” is used to denote a phenyl or naphthyl group each optionallysubstituted by one or more groups, which may be the same or different,selected from hydroxy, linear or branched (C₁-C₆)alkoxy, linear orbranched (C₁-C₆)alkyl, cyano, nitro, amino, trihaloalkyl, or halogenatoms,

the expression “optionally substituted” applied to the terms “alkyl”,“alkenyl” and “alkynyl” denotes that those groups may be substituted byone or more groups, which may be the same or different, selected fromhydroxy, linear or branched (C₁-C₆)alkoxy, aryl, or halogen atoms,

the expression “optionally substituted” applied to the terms“cycloalkyl” and “cycloalkylalkyl” denotes that the cyclic moiety may besubstituted by one or more groups, which may be the same or different,selected from hydroxy, linear or branched (C₁-C₆)alkoxy, oxo, or halogenatoms,

their enantiomers and diastereoisomers, and addition salts thereof witha pharmaceutically acceptable acid or base.

The preferred compounds of the invention are those wherein A forms withthe groups to which it is bonded a tricyclic system of formula A₁.

The preferred values for n are 0, 1 and 2.

More especially, the invention relates to compounds wherein A forms withthe groups to which it is bonded a tricyclic system of formula Alwherein X represents a (CH₂)_(q) group (wherein q is as definedhereinbefore) or a —CH═CH— group, such as, for example, a2,3-dihydrophenalene, 1,2-dihydroacenaphthylene or7,8,9,10-tetrahydrocyclohepta[de]naphthalene tricyclic system.

The preferred values for p are 0, 1 and 2.

The preferred substituents R² and R³ of the invention are a hydrogenatom and alkoxy and alkyl groups.

The preferred R¹ group of the invention is a hydrogen atom.

Advantageously, the invention relates to compounds substituted by the

chain in the a or c position and more especially to those compoundswherein p represents an integer 0 (in which case the bond is single), 1or 2.

The preferred B groups of the invention are the NHCOR⁵ group wherein R⁵is as defined hereinbefore (such as, for example, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl groups),

and the CONHR⁶ group wherein R⁶ is as defined hereinbefore (such as, forexample, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl orarylalkyl groups).

More advantageously, the invention relates to the 2,3-dihydrophenalene,1,2-dihydroacenaphthylene or7,8,9,10-tetrahydrocyclohepta[de]naphthalene tricyclic systems, eachunsubstituted or substituted on the naphthalene moiety by one or morealkoxy or alkyl groups, and substituted in the a or c position by a

group wherein B represents an NHCOR⁵ or CONHR⁶ group (wherein R⁵ and R⁶are as defined hereinbefore).

More especially, the invention relates to the 1,2-dihydroacenaphthyleneor 7,8,9,10-tetrahydrocyclohepta[de]naphthalene tricyclic systems,

each unsubstituted or substituted on the naphthalene moiety by one ortwo alkoxy groups (for example a methoxy group), and substituted in thea or c position by a ═CH—B, ═CH—CH₂—B, —B, —CH₂—B or —(CH₂)₂—B groupwherein B represents an NHCOR⁵ or CONHR⁶ group wherein R⁵ and R⁶represent an alkyl, alkenyl, alkynyl, trihaloalkyl, cycloalkyl,cycloalkylalkyl, aryl or arylalkyl group, such as, for example, methyl,ethyl, propyl, isopropyl, butyl, pentyl, hexyl, vinyl, propargyl,trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,phenyl, naphthyl or benzyl.

Very advantageously, the invention relates to 2,3-dihydrophenalenecompounds, unsubstituted or substituted on the naphthalene moiety by oneor two alkoxy groups (for example a methoxy group),

and substituted in the a or c position by a ═CH—B, ═CH—CH₂—B, —CH₂—B or—(CH₂)₂—B group wherein B represents an NHCOR⁵ or CONHR⁶ group whereinR⁵ and R⁶ represent an alkyl, alkenyl, alkynyl, trihaloalkyl,cycloalkyl, cycloalkylalkyl, aryl or arylalkyl group, such as, forexample, methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, vinyl,propargyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, phenyl, naphthyl or benzyl.

Even more advantageously, the invention relates toN-[(4-methoxy-2,3-dihydro-1H-1-phenalenyl)methyl]acetamide,N-[(4-methoxy-2,3-dihydro-1H-phenalenyl)methyl]propionamide,N-[(4-methoxy-2,3-dihydro-1H-1-phenalenyl)methyl]cyclopropanecarboxamide,N-[(4-methoxy-2,3-dihydro-1H-1-phenalenyl)methyl]butanamide,N-[2-(4-methoxy-2,3-dihydro-1H-1-phenalenyl)ethyl]acetamide,N-[2-(4-methoxy-2,3-dihydro-1H-1-phenalenyl)ethyl]propanamide,N-[2-(4-methoxy-2,3-dihydro-1H-1-phenalenyl)ethyl]-1-cyclopropanecarboxamide,N-(8-methoxy-1,2-dihydro-1-acenaphthylenyl)acetamide,N-[(4-methoxy-2,3-dihydro-1H-1-phenalenyl)methyl]butanamide,N-[2-(9-methoxy-2,3-dihydro-1H-1-phenalenyl)ethyl]acetamide,N-[2-(9-methoxy-2,3-dihydro-1H-1-phenalenyl)ethyl]butanamide,N-[2-(4-methoxy-2,3-dihydro-1H-1-phenalenyl)ethyl]butanamide,N-[2-(4,9-dimethoxy-2,3-dihydro-1H-1-phenalenyl)ethyl]propanamide,N-[2-(4,9-dimethoxy-2,3-dihydro-1H-1-phenalenyl)ethyl]butanamide,N-[2-(4,9-dimethoxy-2,3-dihydro-1H-1-phenalenyl)ethyl]-1-cyclopropanecarboxamide,N-[2-(4,9-dimethoxy-2,3-dihydro-1H-1-phenalenyl)ethyl]acetamide,N-[2-(9-methoxy-2,3-dihydro-1H-1-phenalenyl)methyl]-acetamide,N-[2-(9-methoxy-2,3-dihydro-1H-1-phenalenyl)methyl]butanamide,N-[2-(4,9-dimethoxy-2,3-dihydro-1H-1-phenalenyl)methyl]acetamide,N-[2-(4,9-dimethoxy-2,3-dihydro-1H-1-phenalenyl)methyl]propanamide,N-[2-(4,9-dimethoxy-2,3-dihydro-1H-1-phenalenyl)methyl]butanamide,N-[2-(4,9-dimethoxy-2,3-dihydro-1H-1-phenalenyl)-methyl]-1-cyclopropanecarboxamide,(E)-N-methyl-2-(4-methoxy-2,3-dihydro-1H-1-phenalenylidene)acetamide,(Z)-N-methyl-2-(4-methoxy-2,3-dihydro-1H-1-phenalenylidene)acetamide,N-(1,2-dihydro-1-acenaphthylenylmethyl)acetamide,N-(1,2-dihydro-1-acenaphthylenylmethyl)propanamide,N-(1,2-dihydro-1-acenaphthylenylmethyl)butanamide,N-(1,2-dihydro-1-acenaphthylenylmethyl-1-cyclopropane-carboxamide,N-(8-methoxy-1,2-dihydro-1-acenaphthylmethyl)acetamide,N-(8-methoxy-1,2-dihydro-1-acenaphthylmethyl)propanamide,N-(8-methoxy-1,2-dihydro-1-acenaphthylmethyl)-1-cyclopropanecarboxamide,N-(8-methoxy-1,2-dihydro-1-acenaphthylmethyl)butanamide,N-[2-(1,2-dihydro-1-acenaphthyl)ethyl]acetamide,N-[2-(1,2-dihydro-1-acenaphthyl)ethyl]propanamide,N-[2-(1,2-dihydro-1-acenaphthyl)ethyl]butanamide,N-[2-(1,2-dihydro-1-acenaphthyl)ethyl]cyclopropanecarboxamide,N-[2-(8-methoxy-1,2-dihydro-1-acenaphthyl)ethyl]acetamide,N-[2-(8-methoxy-1,2-dihydro-1-acenaphthyl)ethyl]propanamide,N-[2-(8-methoxy-1,2-dihydro-1-acenaphthyl)ethyl]butanamide,N-[2-(8-methoxy-1,2-dihydro-1-acenaphthyl)ethyl]-1-cyclopropanecarboxamide,N-[2-(1-methoxy-7,8,9,10-tetrahydrocyclohepta[de]naphthalen-7-ylidene)ethyl]propanamide.

The enantiomers and diastereoisomers of the preferred compounds of theinvention and addition salts thereof with a pharmaceutically acceptableacid or base form an integral part of the present invention.

The invention relates also to a process for the preparation of thecompounds of formula (I) wherein A forms with the groups to which it isbonded a tricyclic system of formula (A₁), which process ischaracterised in that there is used as starting material

a compound of formula (II):

 wherein R², R³, R⁵, X, m, m′ and the symbol are as definedhereinbefore,

Y² represents a (CH₂)_(q) group (wherein q is 1, 2 or 3, or q is 0 whenthe symbol is a single bond),

Y¹ represents a (CH₂)_(q′) group (wherein q′ is 0, 1, 2 or 3),substituted by an R¹ group as defined hereinbefore,

Y³ represents a (CH₂)_(q″) group (wherein q″ is 0, 1, 2 or 3),substituted by an R¹ group as defined hereinbefore, where q′+q″≦3 and R¹must represent a hydrogen atom in at least one of the two groups Y¹ andY³,

which is cyclised in a basic medium to yield a compound of formula(III):

wherein R², R³, R⁵, X, Y¹, Y², Y³, m, m′ and the symbol as definedhereinbefore,

which is then reacted with a Lewis acid to obtain a compound of formula(I/a), which is a particular case of the compounds of formula (I):

wherein R², R³, R⁵, X, Y¹, Y², Y³, m, m′ and the symbol are as definedhereinbefore, which is then reduced to obtain a compound of formula(I/b), which is a particular case of the compounds of formula (I):

wherein R², R³, R⁵, X, Y¹, Y², Y³, m, m′ and the symbol are as definedhereinbefore,

or a compound of formula (IV):

wherein R², R³, R⁵, X, Y¹, Y², Y³, m, m′ and the symbol are as definedhereinbefore,

which is successively

cyclised

reacted with a Lewis acid

to yield a compound of formula (I/c), which is a particular case of thecompounds of formula (I):

wherein R², R³, R⁵, X, Y¹, Y², Y³, m, m′ and the symbols are as definedhereinbefore, which is reduced to obtain a compound of formula (I/d),which is a particular case of the compounds of formula (I):

wherein R², R³, R⁵, X, Y¹, Y², Y³, m, m′ and the symbol are as definedhereinbefore,

the totality of the compounds (I/a), (I/b), (I/c) and (I/d) constitutingthe compounds of formula (I/e), a particular case of the compounds offormula (I):

wherein R¹, R², R³, R⁵, n, p, X, m, m′ and the symbol are as definedhereinbefore,

which is either:

subjected to the action of a compound of formula (V): R′_(a)—W (V)wherein R′_(a) may have any of the meanings of the R_(a) group asdefined hereinbefore with the exception of a hydrogen atom, and Wrepresents a leaving group, such as a halogen atom or a tosyl group, toyield a compound of formula (I/f), which is a particular case of thecompounds of formula (I):

wherein R¹, R², R³, R⁵, R′_(a), n, p, X, m, m′ and the symbol are asdefined hereinbefore, the totality of the compounds of formulae (I/e)and (I/f) constituting the compounds of formula (I/g):

wherein R¹, R², R³, R⁵, R_(a), n, p, X, m, m′ and the symbol are asdefined hereinbefore, which may be subjected to the action of athionisation agent, such as Lawesson's reagent, to obtain a compound offormula (I/h), which is a particular case of the compounds of formula(I):

wherein R¹, R², R³, R⁵, R_(a), n, p, X, m, m′ and the symbol are asdefined hereinbefore,

or hydrolysed in a basic medium to yield a compound of formula (VI):

wherein R¹, R², R³, n, p, X, m, m′ and the symbol are as definedhereinbefore,

which is either:

subjected to the action of a pyrylium salt to yield a compound offormula (VII):

wherein Hal represents a halogen atom and R¹, R², R³, n, p, X, m, m′ andthe symbol are as defined hereinbefore,

which is condensed with a cyanide salt to obtain a compound of formula(VIII):

wherein R¹, R², R³, n, p, X m, m′ and the symbols are as definedhereinbefore,

which is hydrolysed in an acidic or basic medium to yield a compound offormula (IX):

wherein R¹, R², R³, n, p, X, m, m′ and the symbol are as definedhereinbefore,

which is subjected, after activation to the acid chloride or in thepresence of a coupling agent, to the action of an amine HNR⁶R⁷ to yielda compound of formula (I/i), which is a particular case of the compoundsof formula (I):

wherein R¹, R², R³, R⁶, R⁷, n, p, X, m, m′ and the symbol are as definedhereinbefore,

which may be subjected to the action of a thionisation agent, such asLawesson's reagent, to obtain a compound (I/j), which is a particularcase of the compounds of formula (I):

wherein R¹, R², R³, R⁶, R⁷, n, p, X, m, m′ and the symbol are as definedhereinbefore,

or subjected to the action of a compound of formula (X):

Z═C═NR⁶R⁷  (X)

wherein Z, R⁶ and R⁷ are as defined hereinbefore, to yield a compound offormula (I/k), which is a particular case of the compounds of formula(I):

wherein R¹, R², R³, R⁶, R⁷, n, p, Z, m, m′ and the symbol are as definedhereinbefore, which may be condensed with a compound of formula (V) toyield a compound of formula (I/l), which is a particular case of thecompounds of formula (I):

wherein R¹, R², R³, R⁶, R⁷, R′_(a), n, p, X, Z, m, m′ and the symbol areas defined hereinbefore,

which compounds (I/a) to (I/l) can be purified according to aconventional separation technique, are converted, if desired, into theiraddition salts with a pharmaceutically acceptable acid or base, andseparated, where appropriate, into their isomers according to aconventional separation technique.

The invention relates also to a process for the preparation of compoundsof formula (I) wherein A forms with the groups to which it is bonded atricyclic system of formula (A₂), (A₃) or (A₄), which process ischaracterised in that there is used as starting material:

a compound of formula (XI):

 wherein R², R⁵, Y², m and the symbol are as defined hereinbefore, and

Y^(′1) represents a (CH₂)_(q′) group substituted by an R¹ group whereinq′ and R¹ are as defined hereinbefore,

Y^(′3) represents a (CH₂)_(q″) group substituted by an R¹ group whereinq″ and R¹ are as defined hereinbefore, where 0≦(q′+q″)≦4 and R¹ mustrepresent a hydrogen atom in at least one of the two groups Y′¹ and Y′³,

and D forms, with the benzene ring, one of the three structures(A_(2a)), (A_(3a)) and (A_(4a)):

wherein X, R², R³, m, m′ and the symbol are as defined hereinbefore,

which is successively

cyclised

reacted with a Lewis acid

to obtain a compound of formula (I/m), which is a particular case of thecompounds of formula (I):

wherein R², R⁵, D, Y¹, Y², Y^(′3), m and the symbol are as definedhereinbefore,

which may be reduced to yield a compound of formula (I/n), which is aparticular case of the compounds of formula (I):

wherein R², R⁵, D, Y^(′1), Y′², Y^(′3), m and the symbol are as definedhereinbefore,

or a compound of formula (XII):

wherein R², R⁵, D, Y^(′1), Y², Y^(′3), m and the symbol are as definedhereinbefore,

which is successively

cyclised

reacted with a Lewis acid

to yield a compound of formula (I/o), which is a particular case of thecompounds of formula (I):

wherein R², R⁵, D, Y^(′1), Y², Y^(′3), m and the symbol are as definedhereinbefore,

which may be reduced to yield a compound of formula (I/p), which is aparticular case of the compounds of formula (I):

wherein R², R⁵, D, Y^(′1), Y², Y^(′3), m and the symbol are as definedhereinbefore, the totality of the compounds (I/m), (I/n), (I/o) and(I/p) constituting the compounds (I/q), a particular case of thecompounds of formula (I):

wherein R¹, R², R⁵, D, n, p, m and the symbol are as definedhereinbefore,

which is either:

subjected to the action of a compound of formula (V) to yield a compoundof formula (I/r), which is a particular case of the compounds of formula(I):

wherein R¹, R², R⁵, R′_(a), D, n, p, m and the symbol are as definedhereinbefore,

the totality of the compounds (I/q) and (I/r) constituting the compounds(I/s), a particular case of the compounds of formula (I):

wherein R¹, R², R⁵, R_(a), D, n, p, m and the symbol are as definedhereinbefore, which may be subjected to the action of a thionisationagent, such as Lawesson's reagent, to obtain a compound of formula(I/t), which is a particular case of the compounds of formula (I):

or hydrolysed in a basic medium to yield a compound of formula (XIII):

wherein R¹, R², D, n, p, m and the symbol are as defined hereinbefore,

which is either:

subjected successively (as for the synthesis of the compound of formula(I/i) starting from a compound of formula (VI))

to the action of a pyrylium salt

to the action of a cyanide salt

to acidic or basic hydrolysis

to condensation, after activation or in the presence of a couplingagent, with an amine HNR⁶R⁷ to yield a compound of formula (I/u), whichis a particular case of the compounds of formula (I):

wherein R¹, R², R⁶, R⁷, D, n, p, m and the symbol are as definedhereinbefore,

which may be subjected to the action of a thionisation agent, such asLawesson's reagent, to obtain a compound of formula (I/v), which is aparticular case of the compounds of formula (I):

wherein R¹, R², R⁶, R⁷, D, n, p, m and the symbol are as definedhereinbefore,

or subjected to the action of a compound of formula (X) to yield acompound of formula (I/w), which is a particular case of the compoundsof formula (I):

wherein R¹, R², R⁶, R⁷, D, Z, n, p, m and the symbol are as definedhereinbefore,

which may be condensed with a compound of formula (V) to yield acompound of formula (I/x), which is a particular case of the compoundsof formula (I):

wherein R¹, R², R⁶, R⁷, R′_(a), D, Z, n, p, m and the symbol are asdefined hereinbefore,

which compounds (I/m) to (I/x) can be purified according to aconventional separation technique, are converted, if desired, into theiraddition salts with a pharmaceutically acceptable acid or base, andseparated, where appropriate, into their isomers according to aconventional separation technique.

Moreover, the compounds of formulae (I/a) to (I/l), which are particularcases of the compounds of formula (I) substituted by the

chain in the a or c position can be obtained by a preparation processwhich is characterised in that there is used as starting material acompound of formula (XIV):

wherein R², R³, X, m and m′ are as defined hereinbefore and T and T′,which are different, represent a hydrogen atom or a —CHO group,

which is subjected to a Wittig reaction and then to catalytic reductionto obtain a compound of formula (XV):

wherein R², R³, X, m and m′ are as defined hereinbefore and T′₁ and T₁represent a hydrogen atom or a group of formula (XVI):

wherein G represents a (CH₂)_(n′) group wherein n′=1, 2 or 3 optionallysubstituted by an R¹ group as defined hereinbefore, with the provisothat one of the two groups T′₁ and T₁ represents a hydrogen atom,

which is successively hydrolysed in a basic medium and thendecarboxylated by heating to yield a compound of formula (XVII):

wherein R², R³, X, m and m′ are as defined hereinbefore and T′₂ and T₂represent a hydrogen atom or a group of formula (XVIII):

wherein G is as defined hereinbefore, with the proviso that one of thetwo groups T′₂ and T₂ represents a hydrogen atom,

which is subjected to cyclisation in the presence of a Lewis acid afteractivation to the oxalyl chloride, to yield a compound of formula (XIX):

wherein R², R³, X, G, m and m′ are as defined hereinbefore, and T′₃ andT₃, which are different, represent a hydrogen atom or an oxo group,which is subjected either:

to a Wittig reaction (optionally followed by reduction) and then tohydrolysis to yield a compound of formula (XX):

wherein R², R³, X, G, m, m′ and the symbol are as defined hereinbefore,and each of T₄ and T′₄ represents a hydrogen atom or forms, with thecarbon atom carrying it,

group wherein p₁ is 1, 2 or 3, with the proviso that one of the twogroups T₄ and T′₄ represents a hydrogen atom,

or successively

to reduction to the corresponding alcohol

to halogenation in the presence of SOCl₂ for example

to condensation with a cyanide salt

to acidic or basic hydrolysis

to yield a compound of formula (XXI):

wherein R², R³, X, G, m, m′ and the symbol are as defined hereinbefore,and T′₅ and T₅, which are different, represent a hydrogen atom or a COOHgroup,

the totality of the compounds (XX) and (XXI) constituting the compoundsof formula (XXII):

wherein R₂, R₃, X, G, m, m′ and the symbol are as defined hereinbefore,and each of T′₆ and T₆ represents a hydrogen atom or forms, with thecarbon atom carrying it,

group wherein p is as defined hereinbefore,

with the proviso that one of the two groups T′₆ and T₆ represents ahydrogen atom,

which compound (XXII) can also be obtained starting from a compound offormula (XIX) by condensation according to a Wittig reaction with acompound containing a nitrile group (followed by optional reduction ofthe double bond), and hydrolysis of the nitrile, which compound (XXII)is either:

subjected, after activation to the acid chloride or in the presence of acoupling agent, to the action of an amine HNR⁶R⁷ to yield a compound offormula (I/y), which is a particular case of the compounds of formula(I):

wherein R², R³, X, G, m, m′ and the symbol are as defined hereinbefore,and each of T′₇ and T₇ represents a hydrogen atom or forms, with thecarbon atom carrying it,

group wherein p, R⁶ and R⁷ are as defined hereinbefore,

with the proviso that one of the two groups T′₇ and T₇ represents ahydrogen atom,

which may be subjected to the action of a thionisation agent, such asLawesson's reagent, to obtain a compound (I/z), which is a particularcase of the compounds of formula (I):

wherein R², R³, X, G, m, m′ and the symbol are as defined hereinbefore,and each of T′₈ and T₈ represents a hydrogen atom or forms, with thecarbon atom carrying it,

group wherein p, R⁶ and R⁷ are as defined hereinbefore,

with the proviso that one of the two groups T₈ and T′₈ represents ahydrogen atom,

or activated to the acid chloride, and then treated with an azide,heated to the corresponding isocyanate and then hydrolysed to yield acompound of formula (XXIII):

wherein R², R³, X, G, m, m′ and the symbol are as defined hereinbefore,and each of T′₉ and T₉ represents a hydrogen atom or forms, with thecarbon atom carrying it,

group wherein p is as defined hereinbefore,

with the proviso that one of the two groups T₉ and T′₉ represents ahydrogen atom,

which compound of formula (XXIII) can also be obtained starting from acompound of formula (XIX) by condensation according to a Wittig reactionwith a compound containing a nitrile group followed by reduction of thenitrile,

which compound of formula (XXIII) is condensed with:

an acyl chloride ClCOR⁵ or the corresponding acid anhydride (mixed orsymmetrical) wherein R⁵ is as defined hereinbefore, to yield a compoundof formula (I/aa), which is a particular case of the compounds offormula (I):

wherein R², R³, X, G, m, m′ and the symbol are as defined hereinbefore,and each of T′₁₀ and T₁₀ represents a hydrogen atom or forms, with thecarbon atom carrying it,

group wherein p and R⁵ are as defined hereinbefore,

with the proviso that one of the two groups T′₁₀ and T₁₀ represents ahydrogen atom,

which may be subjected to the action of a thionisation agent, such asLawesson's reagent, and/or substituted after the action of a compound offormula (V) to yield a compound of formula (I/ab), which is a particularcase of the compounds of formula (I):

wherein R², R³, X, G, m, m′ and the symbol are as defined hereinbefore,and each of T′₁₁ and T₁₁ represents a hydrogen atom or forms, with thecarbon atom carrying it,

group wherein p, R_(a), R⁵ and Z are as defined hereinbefore,

with the proviso that one of the two groups T′₁₁ and T₁₁ represents ahydrogen atom,

which compounds (I/y) to (I/ab) can be purified according to aconventional separation technique, are converted, if desired, into theiraddition salts with a pharmaceutically acceptable acid or base, andseparated, where appropriate, into their isomers according to aconventional separation technique.

The compounds (I/m) to (I/v) can also be obtained according to a similarprocess which is characterised in that there is used as startingmaterial a compound of formula (XXIV):

wherein R₂, D and m are as defined hereinbefore.

The starting materials are:

commercially available,

readily available to the person skilled in the art by using conventionalchemical reactions, or

described in the literature, such as, for example, in Application EP 737670.

The compounds of the invention and the pharmaceutical compositionscontaining them have proved to be useful in the treatment of disordersof the melatoninergic system. The pharmacological study of the compoundsof the invention has in fact shown them to be atoxic, to have very highselective affinity for melatonin receptors and to have significantactivities in respect of the central nervous system and, in particular,therapeutic properties in respect of sleep disorders, anxiolytic,antipsychotic and analgesic properties and properties in respect ofmicrocirculation have been found, enabling it to be established that thecompounds of the invention are useful in the treatment of stress, sleepdisorders, anxiety, seasonal affective disorders, cardiovascularpathologies, insomnia and fatigue due to jetlag, schizophrenia, panicattacks, melancholia, appetite disorders, obesity, insomnia, psychoticdisorders, epilepsy, diabetes, Parkinson's disease, senile dementia,various disorders associated with normal or pathological ageing,migraine, memory loss and Alzheimer's disease, and in cerebralcirculation disorders. In another field of activity, the compounds ofthe invention appear, in treatment, to have ovulation-inhibiting andimmunomodulating properties and they appear to be able to be used in thetreatment of cancers.

The compounds will preferably be used in the treatment of seasonalaffective disorders, sleep disorders, cardiovascular pathologies,insomnia and fatigue due to jetlag, appetite disorders and obesity. Forexample, the compounds will be used in the treatment of seasonalaffective disorders and sleep disorders.

The present invention relates also to pharmaceutical compositionscomprising at least one compound of formula (I) on its own or incombination with one or more pharmaceutically acceptable excipients.

Amongst the pharmaceutical compositions according to the invention theremay be mentioned more especially those that are suitable for oral,parenteral, nasal, per- or trans-cutaneous, rectal, perlingual, ocularor respiratory administration and especially tablets or dragees,sublingual tablets, sachets, paquets, gelatin capsules, glossettes,lozenges, suppositories, creams, ointments, dermal gels, and drinkableor injectable ampoules.

The dosage varies according to the sex, age and weight of the patient,the route of administration, the nature of the therapeutic indication,or of any associated treatments and ranges from 0.01 mg to 1 g per 24hours in 1 or more administrations.

The following Examples illustrate the invention but do not limit it inany way. The following Preparations yield synthesis intermediates foruse in the preparation of the compounds of the invention.

PREPARATION 1 (4-Methoxy-2,3-dihydro-1H-1-phenalenyl)methylamine

Step A: Diethyl2-[(2-methoxy-1-naphthyl)methylene]malonate

2-Methoxy-1-naphthaldehyde (25 g, 1.34.10⁻¹ mol) in benzene (200 ml) isheated for 20 hours at reflux in the presence of diethyl malonate (25ml, 1.65.10⁻¹ mol, 1.23 eq.) and piperidine (2 ml, 2.02.10⁻² mol, 0.15eq.) in a Dean-Stark apparatus. After adding a few additional drops ofpiperidine, the mixture is returned to reflux for 20 hours. The reactionmixture is diluted with toluene (200 ml) and washed with water (125 ml).After separation of the phases, the organic phase is treated with a 1Nhydrochloric acid solution (190 ml), then with a saturated NaHCO₃solution (125 ml) and with a saturated NaCl solution (125 ml). Afterdrying over MgSO₄ and evaporation under reduced pressure, the oilobtained is recrystallised from cyclohexane.

Melting point: 86° C.; Elemental microanalysis:

C H % calculated 69.50 6.14 % found 69.53 6.23

Step B: Diethyl2-[(2-methoxy-1-naphthyl)methyl]malonate

After being solubilised in ethanol (510 ml), the unsaturated compoundobtained in Step A (10 g, 3.05.10⁻² mol) is hydrogenated in the presenceof Raney nickel at ambient temperature with vigorous stirring. Thereaction is monitored by TLC and GPC after 4 hours' hydrogenation. Afterit has been established that the starting material has disappeared, thecatalyst is filtered off over Celite and the ethanol is evaporated offunder reduced pressure. The title product is obtained in the form of acolourless oil.

Elemental microanalysis:

C H % calculated 69.07 6.71 % found 69.14 6.76

Step C: 2-[(2-Methoxy-1-naphthyl)methyl]malonic Acid

In a 1 litre single-necked flask, the compound obtained in Step B (20 g,6.05.10⁻² mol) is heated at reflux in the presence of sodium hydroxide(20 g, 5.00.10⁻¹ mol) and water (340 ml) for 4 hours 30 minutes. Aftercooling, the mixture is diluted with 150 ml of water, filtered throughfilter paper and acidified using concentrated hydrochloric acid in thehot state (80-90° C.); the white microspheres formed in the hot stateare filtered off over a frit after complete cooling. The diacid iswashed with cold water. After drying in an oven (110° C.) for one night,the title compound is dried in a desiccator in the presence of P₂O₅.

Melting point: 174-175° C.; Elemental microanalysis:

C H % calculated 65.69 5.15 % found 65.64 5.18

Step D: 3-(2-Methoxy-1-naphthyl)propanoic Acid

Decarboxylation of the diacid obtained in Step C (8.1 g, 2.95.10⁻² mol)is carried out in a 100 ml single-necked flask purged with argon andheated by a metal bath at 165-178° C. until the evolution of gas hasceased. The acid is recrystallised from a CH₂Cl₂/petroleum ethermixture.

Melting point: 131° C.

Step E: 4-Methoxy-2,3-dihydro-1H-phenalenone

In a 250 ml three-necked flask, oxalyl chloride (1.95 ml, 2.19.10⁻² mol,1 eq.) is added dropwise, under argon, to a solution of the acidobtained in Step D (5 g, 2.17.10⁻² mol) in anhydrous dichloromethane(225 ml) at 0° C. A few drops of anhydrous dimethylformamide are thenadded. After 1 hour at 0° C., slight evolution of gas is still observedand the three-necked flask is left at ambient temperature for 40minutes. After return to 0° C., aluminium chloride (7.5 g, 5.62.10⁻²mol, 2.6 eq.) is added using a spatula. The initially yellow solutionbecomes red, orange and then khaki-green. After 15 minutes' stirring at0° C., the mixture is poured into an ice/1N HCl mixture. Afterseparation of the phases and washings of the acidic aqueous phase withdichloromethane, the combined organic phases are washed with water, thentreated with a saturated NaHCO₃ solution and finally washed with asaturated NaCl solution. After drying over MgSO₄ and evaporation underreduced pressure, the yellow oil obtained crystallises in a freezer.

Melting point: 65° C.

Step F: Ethyl2-(4-Methoxy-2,3-dihydro-1H-1-phenalenylidene)acetate

Triethyl phosphonoacetate (3.22 ml, 1.63.10⁻² mol, 1.15 eq) is addeddropwise, under argon, to a suspension, in anhydrous THF (24 ml), of 60%sodium hydride in oil (650 mg, 1.63.10⁻² mol, 1.15 eq.), previouslywashed with pentane. After 50 minutes' stirring at ambient temperature,the compound obtained in Step E (3 g, 1.41.10⁻² mol, 1 eq.), dissolvedin anhydrous THF (20 ml), is added over 10 minutes. The reaction mixtureis stirred for one night at ambient temperature. The mixture is dilutedwith water, filtered over Celite and extracted several times with ether.After drying over MgSO₄ and evaporation under reduced pressure, the oilyresidue is chromatographed using CH₂Cl₂/petroleum ether 60/40. Theorange-yellow oil obtained crystallises at ambient temperature andcorresponds to a mixture of the two E/Z isomers, their average ratio of45/55 being determined by GPC analysis.

Elemental microanalysis: (E/Z mixture);

C H % calculated 76.57 6.43 % found 76.43 6.58

Step G: Ethyl2-(4-Methoxy-2,3-dihydro-1H-1-phenalenyl)acetate

55 mg of PdCl₂ in 5 ml of methanol are treated with 25 mg of sodiumborohydride. After 15 minutes' stirring, the compound obtained in Step F(1 g, 3.54.10-3 mol), diluted with methanol (15 ml), is added. Themixture is purged with argon and placed under hydrogen. The reaction ismonitored by GPC analysis. After 1 hour 30 minutes' hydrogenation, thereaction mixture is filtered over Celite, rinsed and then evaporatedunder reduced pressure.

Step H: 2-(4-Methoxy-2,3-dihydro-1H-1-phenalenyl)acetic Acid

The ester obtained in Step G (2 g, 7.03.10⁻³ mol) is heated at reflux inthe presence of potassium hydroxide (4 g, 7.13.10⁻² mol, 10 eq.), water(16 ml) and methanol (16 ml) for one night. After evaporating off thesolvent, the residue is taken up in water and extracted twice withether. The basic aqueous phase is acidified using concentrated HCl inthe cold state. The acid is extracted with ethyl acetate and dried overMgSO₄. After evaporating off the solvent under reduced pressure, a brownoil which crystallises at ambient temperature is obtained.

Melting point: 120.5° C.; Elemental microanalysis:

C H % calculated 74.98 6.29 % found 74.80 6.34

Step, I: (4-Methoxy-2,3-dihydro-1H-1-phenalenyl)methylamineHydrochloride

In a 100 ml three-necked flask, triethylamine (645 μl, 4.63 mmol. 1.15eq.) is added dropwise to a solution, cooled to 0° C., of the acidobtained in Step H (1.03 g, 4.02 mmol) in a mixture of acetone (17 ml)and water (1 ml). Ethyl chloroformate (500 μl, 5.23 mmol, 1.30 eq.) isthen slowly added at 0° C.; evolution of gas is visible. The mixture isstirred at 0° C. for 30 minutes; after it has been established, on TLC(CH₂Cl₂), that the starting material has disappeared, a solution ofsodium azide (350 mg, 5.23 mmol, 1.30 eq.) in water (1.7 ml) is added at0° C. The mixture is maintained at that temperature for one hour. TLC(CH₂Cl₂) indicates the formation of the azide. The mixture is pouredinto an ice/water mixture and is then extracted with ether. The etherealphases are washed with water, then dried over Na₂SO₄ and evaporated invacuo without heating. After being taken up in 10 ml of anhydroustoluene, the azide is heated at 80° C. until nitrogen is no longerevolved. After evaporating off the toluene, the oil corresponding to theisocyanate is heated at 100° C. together with a 20% hydrochloric acidsolution (8 ml) for 3 hours; the mixture is stirred for one night atambient temperature. The reaction mixture is diluted with water,filtered through filter paper and extracted with ether. The aqueousphase of pH=1 is rendered basic using solid sodium carbonate and thenextracted with ether. The combined ethereal phases are washed with waterand dried over K₂CO₃. After evaporating off the solvent under reducedpressure, the amine is converted into the hydrochloride after beingsolubilised in ether and treated with a 4N ethereal hydrogen chloridesolution.

Melting point: 237° C.; Elemental microanalysis:

C H N % calculated 68.30 6.88 5.31 % found 68.23 6.90 5.25

By proceeding as for Preparation 1, starting from the appropriatelysubstituted aldehyde, Preparations 2 to 18 are obtained.

PREPARATION 2 2,3-Dihydro-1H-1-phenalenylmethylamine PREPARATION 3(4,9-Dimethoxy-2,3-dihydro-1H-1-phenalenyl)methylamine PREPARATION 4(4-Ethyl-2,3-dihydro-1H-1-phenalenyl)methylamine PREPARATION 5(4-Chloro-2,3-dihydro-1H-1-phenalenyl)methylamine PREPARATION 6(6-Methoxy-4,5-dihydro-3H-benzo[cd]isobenzofuran-5-yl)-methylaminePREPARATION 7(6-Methoxy-4,5-dihydro-3H-benzo[cd]isobenzofuran-3-yl)-methylaminePREPARATION 8(6-Ethyl-4,5-dihydro-3H-benzo[cd]isobenzofuran-5-yl)methylaminePREPARATION 9(6-Ethyl-4,5-dihydro-3H-benzo[cd]isobenzofuran-3-yl)methylaminePREPARATION 10(6-Methoxy-4,5-dihydro-3H-naphtho[1,8-bc]thiophen-5-yl)-methylaminePREPARATION 11(6-Methoxy-4,5-dihydro-3H-naphtho[1,8-bc]thiophen-3-yl)-methylaminePREPARATION 12(6-Methoxy-1,3,4,5-tetrahydrobenzo[cd]indol-3-yl)methylamine PREPARATION13 (6-Methoxy-1,3,4,5-tetrahydro-3-acenaphthylenyl)methylaminePREPARATION 14(7-Methoxy-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-yl)-methylaminePREPARATION 15 (6,7-Dihydro-5H-indeno[5,6-b]thiophen-5-yl)methylaminePREPARATION 16 (7,8-Dihydro-6H-indeno[4,5-b]thiophen-6-yl)methylaminePREPARATION 17 (7,8-Dihydro-6H-indeno[4,5-b]thiophen-8-yl)methylaminePREPARATION 18 (7,8-Dihydro-6H-indeno[5,4-b]thiophen-8-yl)methylaminePREPARATION 19 2-(4-Methoxy-2,3-dihydro-1H-1-phenalenyl)ethylamine

Step A: 2-(4-Methoxy-2,3-dihydro-1H-1-phenalenylidene)acetonitrile

Diethyl cyanomethylphosphonate (1.75 ml, 1.08.10⁻² mol. 1.15 eq) isadded dropwise, under argon, to a suspension, in anhydrous THF (15 ml),of 60% sodium hydride in oil (433 mg, 1.08.10⁻² mol, 1.15 eq.),previously washed with pentane. After 50 minutes' stirring at ambienttemperature, the compound obtained in Step E of Preparation 1 (2 g,9.42.10⁻² mol, 1 eq.), dissolved in anhydrous THF (15 ml), is added over10 minutes. The reaction mixture is stirred for one night at ambienttemperature. The mixture is diluted with water, filtered over Celite andextracted several times with ether. After drying over MgSO₄ andevaporating under reduced pressure, the oily residue is chromatographedusing CH₂Cl₂/petroleum ether 60/40. The orange-yellow oil obtainedcrystallises at ambient temperature and corresponds to a mixture of thetwo E/Z isomers in a variable ratio of from 60/40 to 40/60.

Elemental microanalysis:

C H N % calculated 81.68 5.57 5.95 % found 81.62 5.65 5.86

Step B: 2-(4-Methoxy-2,3-dihydro-1H-1-phenalenyl)acetonitrile

The catalyst is prepared starting from 55 mg of PdCl₂ in 5 ml ofmethanol treated with 25 mg of sodium borohydride. After 15 minutes'stirring, the compound obtained in Step A (1 g, 4.25.10⁻³ mol), dilutedwith methanol (15 ml), is incorporated. The mixture is purged with argonand placed under hydrogen. The reaction is monitored by GPC analysis.After 2 hours 30 minutes' hydrogenation, the reaction mixture isfiltered over Celite, rinsed and then evaporated under reduced pressure.The title product is isolated in the form of a colourless oil.

Elemental microanalysis:

C H N % calculated 80.98 6.37 5.90 % found 80.96 6.47 5.91

Step C: 2-(4-Methoxy-2,3-dihydro-1H-1-phenalenyl)ethylamineHydrochloride

The nitrile obtained in Step B (1.26 g, 5.31.10⁻³ mol), diluted withmethanol (15 ml), is hydrogenated at ambient temperature, with vigorousstirring, in the presence of ammonium hydroxide (1 ml) and Raney nickel.48 hours are necessary for the starting material to disappear. Afterfiltering over Celite, then rinsing and evaporating off the solventunder reduced pressure, the amine is taken up in ether and treated witha few drops of 4N ethereal hydrogen chloride. The hydrochloride isrecrystallised from an ethanol/ether mixture.

Melting point: 223° C.; Elemental microanalysis:

C H N % calculated 80.98 6.37 5.90 % found 80.96 6.47 5.91

By proceeding as for Preparation 19, starting from the correspondingketonic intermediate, Preparations 20 to 26 are obtained:

PREPARATION 202-(6-Methoxy-4,5-dihydro-3H-benzo[cd]isobenzofuran-5-yl)-ethylaminePREPARATION 212-(6-Chloro-4,5-dihydro-3H-benzo[cd]isobenzofuran-5-yl)ethyl-aminePREPARATION 222-(6-Methoxy-4,5-dihydro-3H-benzo[cd]isobenzofuran-3-yl)-ethylaminePREPARATION 232-(6-Ethyl-4,5-dihydro-3H-naphtho[1,8-bc]thiophen-3-yl)ethylaminePREPARATION 242-(6-Methoxy-1,3,4,5-tetrahydro-3-acenaphthylenyl)ethylamine PREPARATION25 2-(6-Methoxy-1,3,4,5-tetrahydrobenzo[Cd]indol-3-yl)ethylaminePREPARATION 26 2-(1,3,4,5-Tetrahydrobenzo[cd]indol-3-yl)ethylaminePREPARATION 27 2-(4-Methoxy-2,3-dihydro-1H-phenalenyl)acetic Acid

A mixture of the compound obtained in Step B of Preparation 19 and a 10%sodium hydroxide solution is heated at reflux. The reaction is monitoredby TLC. When the starting material has disappeared, the reaction mixtureis cooled and extracted at a basic pH; the mixture is then acidifiedusing 2N, and then 3N, hydrochloric acid and extracted again. Afterevaporating off the solvents under reduced pressure, the title acid isobtained in the pure form.

By proceeding as for Preparation 27, starting from the correspondingnitrile, Preparations 28 to 31 are obtained:

PREPARATION 28 2-(4-Chloro-2,3-dihydro-1H-1-phenalenyl)acetic AcidPREPARATION 292-(6-Chloro-4,5-dihydro-3H-benzo[cd]isobenzofuran-5-yl)acetic AcidPREPARATION 30 2-(6-Methoxy-1,3,4,5-tetrahydrobenzo[cd]indol-3-yl)aceticAcid PREPARATION 312-(6-Methoxy-1,3,4,5-tetrahydro-3-acenaphthylenyl)acetic AcidPREPARATION 32 3-(4-Methoxy-2,3-dihydro-1H-1-phenalenyl)propylamine

Step A: Ethyl3-(4-methoxy-2,3-dihydro-1H-1-phenalenylidene)propanoate

The procedure is as in Step F of Preparation 1, with replacement of thetriethyl phosphonoacetate with triethyl phosphonopropanoate.

Steps B, C and D are identical to Steps G, H and I of Preparation 1.

Preparation 33 is obtained by proceeding as for Preparation 32, startingfrom the ketone obtained in Preparation 3.

PREPARATION 33 3-(4,9-Dimethoxy-2,3-dihydro-1H-1-phenalenyl)propylaminePREPARATION 34 4-(4-Methoxy-2,3-dihydro-1H-1-phenalenyl)butanoic Acid

Step A: 4-(4-Methoxy-2,3-dihydro-1H-1-phenalenyl)nitrobutane

The ketone obtained in Step E of Preparation 1 is subjected to theconditions of Steps A and B of Preparation 19, with replacement of thediethyl cyanomethylphosphonate with diethyl cyanopropylphosphonate.

Step B: 4-(4-Methoxy-2,3-dihydro-1H-1-phenalenyl)butanoic Acid

Hydrolysis of the nitrile obtained in Step A is carried out under theconditions of Preparation 27.

PREPARATION 35 2-(2,2a,3,4-Tetrahydroindeno[7,1-bc]furan-4-yl)ethylamine

The procedure is as in Preparation 19, starting from2,3-dihydrobenzo[b]furan-3-one.

PREPARATION 362-(2,2a,3,4-Tetrahydroindeno[7,1-bc]thiophen-4-yl)ethylamine

The title compound is obtained by following the procedure of Preparation35, starting from 2,3-dihydrobenzo[b]thiophen-3-one.

PREPARATION 372-(1,6-Dimethoxy-7,8,9,10-tetrahydrocycloheptaidelnaphthalen-7-yl)ethylamine

Step A: Ethyl4-(2,7-dimethoxy-1-naphthyl)-3-butenoate

The procedure is as in Step F of Preparation 1, ethyltriethylphosphonopropanoate being condensed with2,7-dimethoxy-1-naphthaldehyde.

Step B: Ethyl4-(2,7-dimethoxy-1-naphthyl)butanoate

Reduction of the compound obtained in Step A is carried out under theconditions of Step G of Preparation 1.

Step C: 4-(2,7-Dimethoxy-1-naphthyl)butanoic Acid

Hydrolysis of the ester obtained in Step B is carried out under theconditions of Step H of Preparation 1.

Step D:2-(1,6-Dimethoxy-7,8,9,10-tetrahydrocyclohepta[de]naphthalen-7-yl)-ethylamine

The procedure is as in Step E of Preparation 1 and Steps A, B and C ofPreparation 19.

PREPARATION 382-(1-Methoxy-7,8,9,10-tetrahydrocyclohepta[de]naphthalen-7-yl)-methylamine

Step A: 4-(2-Methoxy-1-naphthyl)butanoic Acid

The procedure is as in Steps A, B and C of Preparation 37, starting from2-methoxy-1-naphthaldehyde.

Step B:2-(1-Methoxy-7,8,9,10-tetrahydrocyclohepta[de]naphthalen-7-yl)-methylamine

The procedure is as in Steps E, F, G, H and I of Preparation 1.

PREPARATION 39 6,7,8,9-Tetrahydro-2-thiabenzo[cd]azulen-9-yl-methylamine

The procedure is as in Preparation 38, starting frombenzo[b]thiophene-4-carbaldehyde.

PREPARATION 40(5-Methoxy-6,7,8,9-tetrahydro-2-oxobenzo[cd]azulen-9-yl)-methylamine

The procedure is as in Preparation 38, starting from5-methoxybenzo[b]furan-4-carbaldehyde.

By proceeding as for Preparation 38, starting from the appropriatelysubstituted aldehyde, Preparations 41 to 49 are obtained:

PREPARATION 41 (7-Methoxy-1,2,3,4-tetrahydro-1-anthracenyl)methylaminePREPARATION 42 (6-Methoxy-1,2,3,4-tetrahydro-1-anthracenyl)methylaminePREPARATION 43(5,6,7,8-Tetrahydronaphtho[2,3-b]thiophen-5-yl)methylamine PREPARATION44 (3-Ethyl-5,6,7,8-tetrahydronaphtho[2,3-b]thiophen-5-yl)methyl-aminePREPARATION 45(6,7,8,9-Tetrahydronaphtho[1,2-b]thiophen-6-yl)methylamine PREPARATION46 (6,7,8,9-Tetrahydronaphtho[1,2-b]thiophen-9-yl)methylaminePREPARATION 47(6,7,8,9-Tetrahydronaphtho[2,1-b]thiophen-9-yl)methylamine PREPARATION48 (1-Methoxy-6,7,8,9-tetrahydronaphtho[2,1-b]thiophen-9-yl)-methylaminePREPARATION 49(1-Methoxy-6,7,8,9-tetrahydronaphtho[1,2-b]thiophen-9-yl)-methylaminePREPARATION 50 (3-Methoxy-2,3-dihydro-1H-1-phenalenyl)methylamine

The procedure is as for Preparation 2, with methanol being added ontothe double bond of the diethyl 2-(1-naphthylmethylene)malonate obtainedin Step A. Preparations 51 to 61 are obtained according to the methodsdescribed in Patent Application EP 737 670.

PREPARATION 513-(3,8-Dimethoxy-1,2-dihydro-1-acenaphthylenyl)propylamine PREPARATION52 4-(3,8-Dimethoxy-1,2-dihydro-1-acenaphthylenyl)butanoic AcidPREPARATION 53 (4-Methoxy-2,3-dihydro-1H-2-phenalenyl)methylaminePREPARATION 54 (4-Ethyl-2,3-dihydro-1H-2-phenalenyl)methylaminePREPARATION 55 2-(4,9-Dimethoxy-2,3-dihydro-1H-2-phenalenyl)acetic AcidPREPARATION 56 4-Methoxy-2,3-dihydro-1H-2-phenalenecarboxylic AcidPREPARATION 57 2-(4-Methoxy-2,3-dihydro-1H-2-phenalenyl)ethylaminePREPARATION 58 3-(4-Methoxy-2,3-dihydro-1H-2-phenalenyl)propylaminePREPARATION 59 (6-Chloro-2,3-dihydro-1H-2-phenalenyl)methylaminePREPARATION 60(1,6-Dimethoxy-7,8,9,10-tetrahydrocyclohepta[de]naphthalen-8-yl)-methylaminePREPARATION 612-(1,6-Dimethoxy-7,8,9,10-tetrahydrocyclohepta[de]naphthalen-8-yl)aceticAcid PREPARATION 62 8-Methoxy-1,2-dihydro-1-acenaphthylenylaminePREPARATION 63 2-(9-Methoxy-2,3-dihydro-1H-1-phenalenyl)acetonitrile

The procedure is as in Steps A and B of Preparation 19.

Melting, point: 116° C.; Elemental microanalysis:

C H N % calculated 80.98 6.37 5.90 % found 80.77 6.47 5.74

PREPARATION 64 2-(4,9-Dimethoxy-2,3-dihydro-1H-1-phenalenyl)ethylamine

The procedure is as in Preparation 19.

PREPARATION 65 (9-Methoxy-2,3-dihydro-1H-1-phenalenyl)methylamine

Step A: 2-(9-Methoxy-2,3-dihydro-1H-1-phenalenyl)acetic Acid

In a 250 ml single-necked flask, the nitrile obtained in Preparation 63(500 mg, 2.1 1.10⁻³ mol) is heated at reflux in the presence of 30%sodium hydroxide solution (8 ml), methanol (8 ml) and ethanol (8 ml) for48 hours. After cooling, the mixture is poured into an ice/watermixture. The mixture is acidified using hydrochloric acid and extractedthree on times with ethyl acetate and once with dichloromethane. Theorganic phases are washed separately with water and with a saturatedNaCl solution, dried over MgSO₄ and then evaporated under reducedpressure. The title acid is obtained in the form of a pale yellow solid.

Melting point: 147° C.; Elemental microanalysis:

C H % calculated + ⅓ H₂O 73.26 6.40 % found 73.38 6.37

Step B: (9-Methoxy-2,3-dihydro-1H-1-phenalenyl)methylamine

The title product is obtained starting from the acid of Step A (515 mg,2.01.10⁻³ mol) in a mixture of acetone (20 ml) and water (600 μl),triethylamine (322 μl, 2.31.10⁻³ mol, 1.15 eq.) and ethyl chloroformate(250 μl, 2.61.10⁻³ mol, 1.30 eq.). The acyl azide is formed by theaction of a solution of sodium azide (175 mg, 2.61.10⁻³ mol, 1.30 eq.)in water (1 ml). After heating in anhydrous toluene (5 ml), theisocyanate is hydrolysed with a 20% hydrochloric acid solution (6 ml).The mixture is stirred for one night at ambient temperature. Thereaction mixture is diluted with water, filtered through filter paperand extracted with ether. The aqueous phase of pH=1 is rendered basicwith solid sodium carbonate and then extracted with ether. The combinedethereal phases are washed with water and dried over K₂CO₃. Afterevaporating off the solvent under reduced pressure, the amine isconverted into the hydrochloride after being solubilised in ether andtreated with a 4N ethereal hydrogen chloride solution. After drying, thetitle product is obtained in the form of a white solid.

PREPARATION 66 [(E)-2-(4-Methoxy-2,3-dihydro-1H-phenalenyl)]acetic Acid

The trans ester obtained in Step F of Preparation 1 (760 mg, 2.69.10⁻³mol) is heated at reflux in the presence of potassium hydroxide (377 mg,6.73.10⁻³ mol, 2.5 eq.), water (10 ml) and methanol (10 ml) for onenight. After evaporating off the solvent, the residue is taken up inwater and extracted twice with ether. The basic aqueous phase isacidified using concentrated HCl in the cold state. The acid isextracted with ethyl acetate, washed with water and dried over MgSO₄.After evaporating off the solvent under reduced pressure, the titleproduct is obtained in the form of a yellow solid.

Melting point: 208° C.; Elemental microanalysis:

C H % calculated + ⅔ H₂O 72.17 5.80 % found 72.37 5.56

PREPARATION 67 [(Z)-2-(4-Methoxy-2,3-dihydro-1H-phenalenyl)]acetic Acid

The procedure is as in Preparation 66, starting from the cis isomer.

Melting point: 187° C.; Elemental microanalysis:

C H % calculated + ⅓ H₂O 73.83 5.68 % found 73.55 5.63

PREPARATION 68 1,2-Dihydro-1-acenaphthylenylmethylamine

Step A: 1,2-Dihydro-1-acenaphthylenone

In a 1 litre three-necked flask, oxalyl chloride (2.87 ml, 3.22.10⁻²mol, 1 eq.) is added dropwise, under argon, to a solution of(naphth-1-yl)acetic acid (6 g, 3.22.10⁻² mol) in anhydrousdichloromethane (270 ml) at 0° C. A few drops of anhydrousdimethylformamide are then added. After 1 hour at 0° C., slightevolution of gas is still observed and the three-necked flask is left atambient temperature for 40 minutes. After return to 0° C., aluminiumchloride (11.2 g, 8.38.10⁻² mol, 2.6 eq.) is added gradually with aspatula. The solution is stirred for twenty minutes and becomesgreen-black in colour. The mixture is poured into an ice/1N HCl mixture.After separation of the phases and washings of the acidic aqueous phasewith dichloromethane, the combined organic phases are washed with water,then treated with a saturated NaHCO₃ solution and finally washed with asaturated NaCl solution. After drying over MgSO₄ and evaporation underreduced pressure, the title product is obtained in the form of a yellowsolid.

Melting point: 123° C.; Elemental microanalysis:

C H % calculated 85.69 4.79 % found 85.59 4.80

Step B: Ethyl2-(1,2-dihydro-1-acenaphthylenylidene)acetate

Triethyl phosphonoacetate (7.11 ml, 3.58.10⁻² mol, 1.15 eq.) is addeddropwise, under argon, to a suspension, in anhydrous THF (50 ml), of 60%sodium hydride in oil (1.43 g, 3.58.10⁻² mol. 1.15 eq.), previouslywashed with pentane. After 40 minutes' stirring at ambient temperature,the compound obtained in Step A (5.24 g, 3.12.10⁻² mol, 1 eq.),dissolved in anhydrous THF (55 ml), is added over 10 minutes. Thereaction mixture is stirred for one night at ambient temperature, thendiluted with water, filtered over Celite and extracted several timeswith ether. After drying over MgSO₄ and evaporation under reducedpressure, the oily residue is chromatographed on a silica gel columnusing CH₂Cl₂/petroleum ether 50/50. A mixture of the two E/Z isomers isisolated.

Elemental microanalysis:

C H % calculated 80.65 5.92 % found 80.68 5.97

Step C: Ethyl2-(1,2-dihydro-1-acenaphthylenyl)acetate

55 mg of PdCl₂ in 5 ml of methanol are treated with 25 mg of sodiumborohydride. After 15 minutes' stirring, the compound obtained in Step B(1 g, 4.20.10⁻³ mol), diluted with methanol (25 ml), is added. Themixture is purged with argon and placed under a hydrogen atmosphere.After 2 hours 30 minutes' hydrogenation, the reaction mixture isfiltered over Celite, rinsed and then evaporated under reduced pressure.

Step D: 2-(1,2-Dihydro-1-acenaphthylenyl)acetic Acid

The ester obtained in Step C (1.9 g, 7.91.10⁻³ mol) is heated at refluxin the presence of potassium hydroxide (2.34 g, 4.17.10⁻² mol, 5.3 eq.),water (16 ml) and methanol (16 ml) for one night. After evaporating offthe solvent, the residue is taken up in water and extracted twice withether. The basic aqueous phase is acidified using concentrated HCl inthe cold state. The acid is extracted with ethyl acetate and dried overMgSO₄. After evaporating off the solvent under reduced pressure, thetitle compound is obtained in the form of a yellow solid.

Melting point: 123° C.; Elemental microanalysis:

C H % calculated 79.23 5.70 % found 79.12 5.77

Step E: 1,2-Dihydro-1-acenaphthylenylmethylamine

In a 250 ml three-necked flask, triethylamine (3.49 ml, 2.50.10⁻² mol,1.15 eq.) is added dropwise to a solution, cooled to 0° C., of the acidobtained in Step D (4.62 g, 2.18. 10⁻² mol) in a mixture of acetone (95ml) and water (5.4 ml). Ethyl chloroformate (2.71 ml, 2.83.10⁻² mol,1.30 eq.) is then slowly added at 0° C.; evolution of gas is visible.The mixture is stirred at 0° C. for 30 minutes; after it has beenestablished, on TLC (CH₂Cl₂), that the starting material hasdisappeared, a solution of sodium azide (1.89 g, 2.83.10⁻² mol, 1.30eq.) in water (9.2 ml) is added at 0° C. The mixture is maintained atthat temperature for one hour. The mixture is poured into an ice/watermixture and is then extracted with ether. The ethereal phases are washedwith water, then dried over Na₂SO₄ and evaporated in vacuo withoutheating. The acyl azide is taken up in 50 ml of anhydrous toluene andthen heated at 80° C. until nitrogen is no longer evolved. Afterevaporating off the toluene, the oil corresponding to the isocyanate isheated at 100° C. together with a 20% hydrochloric acid solution (52 ml)for 3 hours; the mixture is stirred for one night at ambienttemperature. The reaction mixture is diluted with water, filteredthrough filter paper and extracted with ether. The aqueous phase of pH=1is rendered basic using solid sodium carbonate and is then extractedthree times with dichloromethane. The combined organic phases are washedwith water and dried over K₂CO₃. After evaporating off the solvent underreduced pressure, the amine is obtained in the form of an oil (820 mg).The solid, having been filtered and taken up in dichloromethane, istreated in the same manner as the filtrate. The amine so obtained isconverted into the hydrochloride after being solubilised in ether andtreated with a 4N ethereal hydrogen chloride solution. After drying, thetitle product is obtained in the form of a white solid.

Melting point: >250° C.; Elemental microanalysis:

C H N % calculated 71.07 6.42 6.37 % found 70.84 6.49 6.40

PREPARATION 69 (8-Methoxy-1,2-dihydro-1-acenaphthylenyl)methylamine

The procedure is as in Preparation 68, starting from(7-methoxynaphth-1-yl)acetic acid.

PREPARATION 70 1,2-Dihydro-1-acenaphthylenylethylamine

Step A: (1,2-Dihydro-1-acenaphthylenylidene)acetonitrile

The procedure is as in Step B of Preparation 68, with replacement of thetriethyl phosphonoacetate with diethyl cyanomethylphosphonate.

Elemental microanalysis:

C H N % calculated 87.93 4.74 7.32 % found 87.85 4.79 7.25

Step B: (1,2-Dihydro-1-acenaphthylenyl)acetonitrile

The catalyst is prepared starting from 55 mg of PdCl₂ in 5 ml ofmethanol treated with 25 mg of sodium borohydride. After 15 minutes'stirring, the compound obtained in Step A (1 g, 5.23.10⁻³ mol), dilutedwith methanol (15 ml), is incorporated. The mixture is purged with argonand placed under hydrogen. After 3 days' hydrogenation, the reactionmixture is filtered over Celite, rinsed and then evaporated underreduced pressure. The title product is isolated in the form of a lightbrown oil.

Elemental microanalysis:

C H N % calculated + ⅛ H₂O 86.01 5.80 7.16 % found 85.73 5.87 7.13

Step C: 1,2-Dihydro-1-acenaphthylenylethylamine

The nitrile obtained in Step B (900 mg, 4.66.10⁻³ mol), diluted withmethanol (30 ml), is hydrogenated with vigorous stirring at ambienttemperature in the presence of ammonium hydroxide (2 ml) and Raneynickel. After 23 hours, the starting material has disappeared. Afterfiltering over Celite, then rinsing and evaporating off the solventunder reduced pressure, the title amine is obtained in the form of anoil, which is used without being purified.

PREPARATION 71 (8-Methoxy-1,2-dihydro-1-acenaphthylenyl)ethylamine

The procedure is as in Preparation 70.

Step A: (8-Methoxy-1,2-dihydro-1-acenaphthylenyl)acetonitrile

Step B: (8-Methoxy-1,2-dihydro-1-acenaphthylenyl)ethylamine

Elemental microanalysis:

C H N % calculated 71.07 6.42 6.37 % found 70.84 6.49 6.40

PREPARATION 72 2-(1-Methoxy-7,8,9,10-tetrahydrocycloheptaldelnaphthalen-7-ylidene)acetonitrile

Step A: 3-(2-Methoxynaphth-1-yl)butenoic Acid

A mixture of 2-methoxy-1-naphthaldehyde (2.45 g, 1.32.10⁻² mol, 1 eq.)and (3-triphenyl-phosphonium) propanoic acid bromide (6 g, 1.44.10⁻²mol, 1.1 eq.), solubilised in an anhydrous mixture of THF and DMSO (17ml/17 ml), is added dropwise to a suspension, under argon at 0° C., inanhydrous THF (10 ml) of 60% sodium hydride in oil (1.16 g, 2.90.10⁻²mol, 2.2 eq.), previously washed with pentane. The reaction mixture isstirred for one night at ambient temperature, then diluted with water,filtered over Celite and, after the addition of a few drops of sodiumhydroxide solution, extracted twice with ether. The basic aqueous phaseis acidified using HCl in the cold state. The desired acid is extractedwith ether. After washing the ethereal phase with a saturated NaClsolution, then drying over MgSO₄ and evaporating under reduced pressure,the solid residue is chromatographed on a silica gel column (1. CH₂Cl₂;2. CH₂Cl₂/MeOH:97/3). A white solid corresponding to the mixture of thetwo E/Z isomers of the title compound is obtained.

Melting point: 112° C.; Elemental microanalysis:

C H % calculated 74.36 5.82 % found 74.47 5.90

Step B: 4-(2-Methoxynaphth-1-yl)butanoic Acid

The compound obtained in Step A (3.4 g, 1.40.10⁻² mol) is solubilised inethyl acetate (90 ml) in the presence of 5% palladium-on-carbon. Themixture is purged with argon and placed under a hydrogen atmosphere.After 15 hours' hydrogenation, the reaction mixture is filtered overCelite, rinsed and then evaporated under reduced pressure. The titleproduct is isolated in the form of white crystals.

Melting point: 88° C.; Elemental microanalysis:

C H % calculated 73.75 6.60 % found 73.59 6.71

Step C: 1-Methoxy-7,8,9,10-tetrahydrocyclohepta[de]naphthalen-7-one

The procedure is as in Step E of Preparation 1.

Melting point: 67° C.; Elemental microanalysis:

C H % calculated 79.62 6.24 % found 79.73 6.31

Step D:2-(1-Methoxy-7,8,9,10-tetrahydrocyclohepta[de]naphthalen-7-ylidene)acetonitrile

The procedure is as in Step A of Preparation 19.

Melting point: 96° C.; Elemental microanalysis:

C H N % calculated 81.90 6.06 5.62 % found 81.88 6.18 5.64

EXAMPLE 1 N-[(4-Methoxy-2,3-dihydro-1H-1-phenalenyl)methyl]acetamide

In a 100 ml three-necked flask, the hydrochloride obtained inPreparation 1 (300 mg, 1.14.10⁻³ mol, 1 eq.) is solubilised in atwo-phase CH₂Cl₂/water medium (17 ml/17 ml) in the presence of sodiumcarbonate (854 mg, 7.96.10⁻³ mol, 7 eq.). Acetic anhydride (110 μl,1.17.10⁻³ mol, 1 eq.) is added at 0° C. The reaction mixture is stirredat ambient temperature for 20 minutes. After separation of the phases,washings of the organic phase with a saturated NaHCO₃ solution, waterand then a saturated NaCl solution, drying over MgSO₄ and finallyevaporating off the solvent under reduced pressure, the residue ischromatographed using flash chromatography (1. CH₂Cl₂; 2. CH₂Cl₂/MeOH:99/1). The title compound is isolated in the pure form byrecrystallisation from hexane/AcOEt.

Melting point: 126° C.; Elemental microanalysis:

C H N % calculated 75.81 7.11 5.20 % found 75.64 7.19 5.15

EXAMPLE 2 N-[(4-Methoxy-2,3-dihydro-1H-phenalenyl)methyl]propionamide

The procedure is as in Example 1, with replacement of the aceticanhydride with propionic anhydride.

Melting point: 120° C.; Elemental microanalysis:

C H N % calculated 76.30 7.47 4.94 % found 76.21 7.59 4.89

EXAMPLE 3N-[(4-Methoxy-2,3-dihydro-1H-1-phenalenyl)methyl]cyclopropanecarboxamide

The hydrochloride obtained in Preparation 1 (382 mg, 1.45.10⁻³ mol) istaken up in dichloromethane and treated with ammonium hydroxide untilthe solid has been solubilised and a basic pH has been obtained for theaqueous phase. After separation of the phases, the amine is dried overK₂CO₃. At 0° C., the amine (320 mg, 1.41.10⁻³ mol) is taken up inanhydrous dichloromethane (10 ml) in the presence of triethylamine onpotassium hydroxide (295 μl, 2.12.10⁻³ mol, 1.5 eq.). Cyclopropionylchloride (130 μl, 1.43.10⁻³ mol, 1 eq.) is added dropwise at 0° C. Thereaction mixture is stirred at ambient temperature for minutes. Afterwashings with water, drying over MgSO₄ and then evaporating off thesolvent under reduced pressure, the residue (400 mg) is chromatographedusing flash chromatography (1. CH₂Cl₂; 2. CH₂Cl₂/MeOH: 99/1). The titleproduct is obtained in the pure form by recrystallisation fromhexane/AcOEt.

Melting point: 119° C.; Elemental microanalysis:

C H N % calculated 77.26 7.17 4.74 % found 77.19 7.24 4.70

EXAMPLE 4 N-[(4-Methoxy-2,3-dihydro-1H-1-phenalenyl)methyl]butanamide

The procedure is as in Example 1, with replacement of the aceticanhydride with butanoic anhydride.

Melting point: 100° C.; Elemental microanalysis:

C H N % calculated 76.74 7.80 4.71 % found 76.65 7.89 4.67

EXAMPLE 5N-[(4-Methoxy-2,3-dihydro-1H-1-phenalenyl)methyl]-N-methyl-1-cyclopropanecarboxamide

The compound obtained in Example 3 is reacted in the presence of NaH(1.5 eq) and dimethyl sulphate (1.2 eq). The reaction is monitored usingTLC. When all the starting material has disappeared, the reactionmixture is hydrolysed and then extracted. After evaporating off thesolvents, the title product is isolated by flash chromatography.

EXAMPLE 6N-[(4-Hydroxy-2,3-dihydro-1H-1-phenalenyl)methyl]-N-methyl-cyclopropanecarboxamide

The compound obtained in Example 3 is subjected to demethylation in thepresence of a customary agent such as, for example, BBr₃.

EXAMPLE 7N-[(4-Benzyloxy-2,3-dihydro-1H-1-phenalenyl)methyl]cyclopropanecarboxamide

The compound obtained in Example 6 is reacted in a basic system in thepresence of benzyl chloride.

EXAMPLE 8N-[(4-Allyloxy-2,3-dihydro-1H-1-phenalenyl)methyl]cyclopropane-carboxamide

The procedure is as in Example 7, with replacement of the benzylchloride with allyl chloride.

EXAMPLE 9N-Cyclobutyl-N′-[(4-methoxy-2,3-dihydro-1H-1-phenalenyl)methyl]-urea

The compound of Preparation 1 is suspended in pyridine; then cyclobutylisocyanate is added dropwise and the reaction mixture is heated. Whenthe reaction has ended, the reaction mixture is poured into ice-coldwater and acidified using a 1N hydrochloric acid solution. Aftercustomary treatment, the title compound is isolated in the pure form.

EXAMPLE 10 N-(2,3-Dihydro-1H-1-phenalenylmethyl)-2-iodoacetamide

The procedure is as in Example 1, with 1-iodoacetic anhydride beingcondensed with the compound obtained in Preparation 2.

EXAMPLE 11 N-[(4-Methoxy-2,3-dihydro-1H-1-phenalenyl)methyl]benzamide

The procedure is as in Example 1, with replacement of the aceticanhydride with benzoic anhydride.

EXAMPLE 12N-[(4,9-Dimethoxy-2,3-dihydro-H-1-phenalenyl)methyl]hexanamide

The procedure is as in Example 1, with hexanoic anhydride beingcondensed with the compound obtained in Preparation 3.

EXAMPLE 13N-[(4-Ethyl-2,3-dihydro-1H-1-phenalenyl)methyl]cyclohexane-carboxamide

The procedure is as in Example 1, with cyclohexanecarboxylic anhydridebeing condensed with the compound obtained in Preparation 4.

EXAMPLE 14 N-[(4-Chloro-2,3-dihydro-1H-1-phenalenyl)methyl]heptanamide

The procedure is as in Example 1, with heptanoic anhydride beingcondensed with the compound obtained in Preparation 5.

EXAMPLE 15 N-[(4-Chloro-2,3-dihydro-1H-1-phenalenyl)methyl]acetamide

The procedure is as in Example 1, starting from the compound obtained inPreparation 5.

EXAMPLE 16N-[(6-Methoxy-4,5-dihydro-3H-1-benzo[cd]isobenzofuran-5-yl)methyl]acetamide

The procedure is as in Example 1, starting from the compound obtained inPreparation 6.

EXAMPLE 17N-[(6-Methoxy-4,5-dihydro-3H-benzo[cd]isobenzofuran-5-yl)-methyl]cyclohexanecarboxamide

The procedure is as in Example 16, with replacement of the aceticanhydride with cyclohexanecarboxylic anhydride.

EXAMPLE 18N-[(6-Metboxy-4,5-dihydro-3H-benzo[cd]isobenzofuran-3-yl)methyl]acetamide

The procedure is as in Example 1, starting from the compound obtained inPreparation 7.

EXAMPLE 19N-[(6-Ethyl-4,5-dihydro-3H-benzo[cd]isobenzofuran-5-yl)methyl]pentanamide

The procedure is as in Example 1, with pentanoic anhydride beingcondensed with the compound obtained in Preparation 8.

EXAMPLE 20N-[(6-Ethyl-4,5-dihydro-3H-benzo[cd]isobenzofuran-3-yl)methyl]butanamide

The procedure is as in Example 1, with butanoic anhydride beingcondensed with the compound obtained in Preparation 9.

EXAMPLE 21N-[(6-Methoxy-4,5-dihydro-3H-naphthol[1,8-bc]thiophen-5-yl)methyl]propanamide

The procedure is as in Example 2, starting from the compound obtained inPreparation 10.

EXAMPLE 22N-[(6-Methoxy-4,5-dihydro-3H-naphthol[1.8-bc]thiophen-3-yl)methyl]acetamide

The procedure is as in Example 1, starting from the compound obtained inPreparation 11.

EXAMPLE 23N-[(6-Methoxy-4,5-dihydro-3H-naphtho[1,8-bc]thiophen-3-yl)methyl]-N-methylacctamide

The procedure is as in Example 5, starting from the compound obtained inExample 22.

EXAMPLE 24N-[(6-Methoxy-4,5-dihydro-3H-naphtho[1,8-bc]thiophen-3-yl)methyl]-N-methylethanethioamide

The compound obtained in Example 23 is treated in customary manner withLawesson's reagent.

EXAMPLE 25N-Cyclobutyl-N′-[(6-methoxy-4,5-dihydro-3H-naphtho[1,8-bc]-thiophen-3-yl)methyl]urea

The procedure is as in Example 9, starting from the compound obtained inPreparation 11.

EXAMPLE 26N-[(6-Methoxy-1,3,4,5-tetrahydrobenzo[cd]indol-3-yl)methyl]acetamide

The procedure is as in Example 1, starting from the compound obtained inPreparation 12.

EXAMPLE 27N-[(6-Methoxy-1-methyl-1,3,4,5-tetrahydrobenzo[cd]indol-3-yl)methyl]-N-methylacetamide

The compound obtained in Example 26, dissolved in tetrahydrofuran, isadded dropwise at 0° C. to a suspension of NaH (2.2 eq.) in THF.Dimethyl sulphate (2.3 eq.) is added very slowly at 0° C. and then thereaction mixture is stirred at ambient temperature. When the reactionhas ended, customary treatment is carried out and the title product isisolated by chromatography.

EXAMPLE 28N-[(6-Hydroxy-1-methyl-1,3,4,5-tetrahydrobenzo[cd]indol-3-yl)methyl]-N-methylacetamide

The compound of Example 27, dissolved in dichloromethane, is addeddropwise at 0° C. to a suspension of aluminium chloride and benzylthiol.The reaction is monitored by TLC. When the reaction has ended, thereaction mixture is poured onto ice and then acidified using 1N HCl.Customary extraction is carried out and the title compound is isolatedby chromatography.

EXAMPLE 29N-Methyl-N-1(1-methyl-6-(2-propynyloxy)-1,3,4,5-tetrahydrobenzo-[cd]indol-3-yl)methyl]acetamide

The procedure is as in Example 7, starting from the compound obtained inExample 28 and with replacement of the benzyl chloride with3-chloro-1-propyne.

EXAMPLE 30N-[(6-Methoxy-1,3,4,5-tetrahydro-3-acenaphthylenyl)methyl]-1-cyclopropanecarboxamide

The procedure is as in Example 3, starting from the compound obtained inPreparation 13.

EXAMPLE 31N-[(6-Hydroxy-1,3,4,5-tetrahydro-3-acenaphthylenyl)methyl]-1-cyclopropanecarboxamide

The procedure is as in Example 6, starting from the compound obtained inExample 30.

EXAMPLE 32N-[(6-Benzyloxy-1,3,4,5-tetrahydro-3-acenaphthylenyl)methyl]-1-cyclopropanecarboxamide

The procedure is as in Example 7, starting from the compound obtained inExample 31.

EXAMPLE 33N-[(7-Methoxy-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-yl)methyl]acetamide

The procedure is as in Example 1, starting from the compound obtained inPreparation 14.

EXAMPLE 34 N-(6,7-Dihydro-5H-indeno[5,6-b]thiophen-5-ylmethyl)butanamide

The procedure is as in Example 1, with butanoic anhydride beingcondensed with the compound obtained in Preparation 15.

EXAMPLE 35 N-(7,8-Dihydro-6H-indeno[4,5-b]thiophen-6-ylmethyl)acetamide

The procedure is as in Example 1, starting from the compound obtained inPreparation 16.

EXAMPLE 36 N-(7,8-Dihydro-6H-indeno[4,5-b]thiophen-8-ylmethyl)acetamide

The procedure is as in Example 1, starting from the compound obtained inPreparation 17.

EXAMPLE 37N-(7,8-Dihydro-6H-indeno[5,4,-b]thiophen-8-ylmethyl)-2-chloroacetamide

The procedure is as in Example 1, with chloroacetic anhydride beingcondensed with the compound obtained in Preparation 18.

EXAMPLE 38 N-[2-(4-Methoxy-2,3-dihydro-1H-1-phenalenyl)ethyl]acetamide

The nitrile obtained in Step A of Preparation 19 (440 mg, 1.85.10⁻³mol), diluted with tetrahydrofuran (12 ml), is hydrogenated at ambienttemperature in the presence of acetic anhydride (430 μl, 4.56.10⁻³ mol,2.5 eq.) and Raney nickel. After 8 hours' hydrogenation, the reactionmixture is filtered over Celite, rinsed and evaporated under reducedpressure. The residue is then taken up in dichloromethane and washedwith water, then with a saturated NaHCO₃ solution and subsequently withwater. After drying over MgSO₄ and evaporating off the solvent, theresidue is purified by flash chromatography (CH₂Cl₂/methanol: 99/1).Elemental microanalysis:

C H N % calculated + ¼H₂O 75.10 7.53 4.87 % found 74.95 7.50 4.80

EXAMPLE 39 N-[2-(4-Methoxy-2,3-dihydro-1H-1-phenalenyl)ethyl]propanamide

The nitrile obtained in Step A of Preparation 19 (500 mg, 2.11.10⁻³mol), in tetrahydro-furan (25 ml), is hydrogenated at ambienttemperature in the presence of propionic anhydride (500 μl, 3.90.10⁻³mol, 1.85 eq.) and Raney nickel. After 30 hours' hydrogenation, thereaction mixture is filtered over Celite, rinsed and evaporated underreduced pressure. The residue is then taken up in dichloromethane andwashed with water, then with a saturated NaHCO₃ solution andsubsequently with water. After drying over MgSO₄ and evaporating off thesolvent, the residue having a weight of 650 mg is purified by flashchromatography (CH₂Cl₂/methanol: 99/1). Elemental microanalysis:

C H N % calculated + ¼H₂O 75.59 7.85 4.64 % found 75.54 7.88 4.61

EXAMPLE 40N-[2-(4-Methoxy-2,3-dihydro-1H-1-phenalenyl)ethyl]-1-cyclopropanecarboxamide

The hydrochloride obtained in Preparation 19 (350 mg, 1.26.10⁻³ mol) istaken up in a dichloromethane/water mixture (16 ml/16 ml) in thepresence of sodium carbonate (940 mg). At 0° C., cyclopropionyl chloride(115 μl, 1.27.10⁻³ mol, 1 eq.) is added dropwise. The reaction mixtureis stirred at ambient temperature for 15 minutes. Neutralisation iscarried out by adding a few drops of ammonium hydroxide. After washingswith water, drying over MgSO₄ and then evaporating off the solvent underreduced pressure, the residue is purified using flash chromatography (1.CH₂Cl₂; 2. CH₂Cl₂/MeOH: 99/1).

Melting point: 118° C.; Elemental microanalysis:

C H N % calculated + ¼H₂O 76.52 7.55 4.64 % found 76.55 7.51 4.42

EXAMPLE 41N-[2-(4-Methoxy-2,3-dihydro-1H-1-phenalenyl)ethyl]-4-methoxybenzamide

The procedure is as in Example 40, with replacement of thecyclopropionyl chloride with 4-methoxy-benzoyl chloride.

EXAMPLE 42N-[2-(4-Methoxy-2,3-dihydro-1H-1-phenalenyl)ethyl]-3-chlorobenzamide

The procedure is as in Example 41, with replacement of thecyclopropionyl chloride with 3-chloro-benzoyl chloride.

EXAMPLE 43N-[2-(4-Methoxy-2,3-dihydro-1H-1-phenalenyl)ethyl]propanethioamide

The title compound is obtained by subjecting the compound of Example 39to Lawesson's reagent.

EXAMPLE 44N-[2-(4-Methoxy-2,3-dihydro-1H-1-phenalenyl)ethyl]-3-butenamide

The procedure is as in Example 40, with replacement of the propionylchloride with butenoyl chloride.

EXAMPLE 45 N-[2-(4-Hydroxy-2,3-dihydro-1H-1-phenalenyl)ethyl]acetamide

The procedure is as in Example 6, starting from the compound obtained inExample 38.

EXAMPLE 46N-[2-(4-Cyclopropyloxy-2,3-dihydro-1H-1-phenalenyl)ethyl]-acetamide

The procedure is as in Example 7, with replacement of the benzylchloride with cyclopropyl chloride.

EXAMPLE 47N-[2-(6-Methoxy-4,5-dihydro-3H-benzo[cd]isobenzofuran-5-yl)ethyl]butanamide

The procedure is as in Example 38, with butanoyl chloride beingcondensed with the compound obtained in Preparation 20.

EXAMPLE 48N-Butyl-N-[2-(6-methoxy-4,5-dihydro-3H-benzo[cd]isobenzofuran-5-yl)ethyl]acetamide

The procedure is as in Example 5, starting from the compound of Example38 and with replacement of the methyl sulphate with butyl iodide.

EXAMPLE 49N-[2-(6-Chloro-4,5-dihydro-3H-benzo[cd]isobenzofuran-5-yl)ethyl]-acetamide

The procedure is as in Example 38, starting from the compound obtainedin Preparation 21.

EXAMPLE 50N-[2-(6-Methoxy-4,5-dihydro-3H-benzo[cd]isobenzofuran-3-yl)ethylibutanamide

The procedure is as in Example 47, starting from the compound obtainedin Preparation 22.

EXAMPLE 51N-Hexyl-N-[2-(6-methoxy-4,5-dihydro-3H-benzo[cd]isobenzofuran-3-yl)ethyl]butanamide

The procedure is as in Example 48, starting from the compound of Example50 and with replacement of the butyl iodide with hexyl iodide.

EXAMPLE 52N-[2-(6-Ethyl-4,5-dihydro-3H-naphtho[1,8-bc]thiophen-3-yl)ethyl]heptanamide

The procedure is as in Example 38, with heptanoyl chloride beingcondensed with the compound obtained in Preparation 23.

EXAMPLE 53N-[2-(6-Methoxy-1,3,4,5-tetrahydro-3-acenaphthylenyl)ethyl]-1-cyclobutanecarboxamide

The procedure is as in Example 38, with cyclobutanoyl chloride beingcondensed with the compound obtained in Preparation 24.

EXAMPLE 54N-[2-(6-Methoxy-1,3,4,5-tetrahydrobenzo[cd]indol-3-yl)ethyl]butanamide

The procedure is as in Example 47, starting from the compound obtainedin Preparation 25.

EXAMPLE 55N-[2-(6-Hydroxy-1,3,4,5-tetrahydrobenzo[cd]indol-3-yl)ethyl]butanamide

The procedure is as in Example 28, starting from the compound obtainedin Example 54.

EXAMPLE 56 N-[2-(1,3,4,5-Tetrahydrobenzo[cd]indol-3-yl)ethyl]acetamide

The procedure is as in Example 38, starting from the compound obtainedin Preparation 26.

EXAMPLE 57N-Cyclobutyl-2-(4-methoxy-2,3-dihydro-1H-1-phenalenyl)ethyl]acetamide

The title product is obtained by condensing N-cyclobutylamine with theacid obtained in Preparation 27 after conversion into the acid chloride.

EXAMPLE 58 N-Propyl-2-(4-methoxy-2,3-dihydro-1H-1-phenalenyl)acetamide

The procedure is as in Example 57, with replacement of theN-cyclobutylamine with N-propylamine.

EXAMPLE 59N-Hexyl-2-(4-chloro-2,3-dihydro-1H-1-phenalenyl)ethyl]acetamide

The procedure is as in Example 57, with N-hexylamine being condensedwith the acid chloride of the compound obtained in Preparation 28.

EXAMPLE 60N-Phenyl-2-(6-chloro-4,5-dihydro-3H-benzo[cd]isobenzofuran-5-yl)-ethyl]acetamide

The procedure is as in Example 57, with N-phenylamine being condensedwith the acid chloride of the compound obtained in Preparation 29.

EXAMPLE 61 N-(2,3,4-Trimethoxyphenyl-2-(6-methoxy-13,4,5-tetrahydrobenzo-[cd]-indol-3-yl)acetamide

The procedure is as in Example 57, with N-(2,3,4-trimethoxyphenyl)aminebeing condensed with the acid chloride of the compound obtained inPreparation 30.

EXAMPLE 62N-Hexyl-2-(6-methoxy-1,3,4,5-tetrahydro-3-acenaphthylenyl)-acetamide

The procedure is as in Example 59, starting from the compound obtainedin Preparation 31.

EXAMPLE 63N-[3-(4-Methoxy-2,3-dihydro-1H-1-phenalenyl)propyl]pentanamide

The procedure is as in Example 19, starting from the compound obtainedin Preparation 32.

EXAMPLE 64N-Methyl-N-[3-(4-methoxy-2,3-dihydro-1H-1-phenalenyl)propyl]pentanamide

The procedure is as in Example 23, starting from the compound obtainedin Example 63.

EXAMPLE 65N-[3-(4,9-Dimethoxy-2,3-dihydro-1H-1-phenalenyl)propyl]acetamide

The procedure is as in Example 38, starting from the compound obtainedin Preparation 33.

EXAMPLE 66N-Cyclopentyl-4-(4-methoxy-2,3-dihydro-1H-1-phenalenyl)butanamide

The procedure is as in Example 57, with N-cyclopentylamine beingcondensed with the acid chloride of the compound obtained in Preparation34.

EXAMPLE 67N-Cyclopentyl-N-methyl-4-(4-methoxy-2,3-dihydro-1H-1-phenalenyl)butanamide

The procedure is as in Example 64, starting from the compound obtainedin Example 66.

EXAMPLE 68N-[2-(2,2a,3,4-Tetrahydroindeno[7,1-bc]furan-4-yl)ethyl]-1-cyclopropanecarboxamide

The procedure is as in Example 40, starting from the compound obtainedin Preparation 35.

EXAMPLE 69N-[2-(2,2a,3,4-Tetrahydroindeno[7,1-bc]thiophen-4-yl)ethyl]acetamide

The procedure is as in Example 38, starting from the compound obtainedin Preparation 36.

EXAMPLE 70 N-[2-(I,6-Dimethoxy-7,8,9,10-tetrahydrocyclohepta[de]naphthalen-7-yl)ethyl]acetamide

The procedure is as in Example 38, starting from the compound obtainedin Preparation 37.

EXAMPLE 71N-[(1-Methoxy-7,8,9,10-tetrahydrocyclohepta[de]naphthalen-7-yl)methyl]acetamide

The procedure is as in Example 38, starting from the compound obtainedin Preparation 38.

EXAMPLE 72N-(6,7,8,9-Tetrahydro-2-thiabenzo[cd]azulen-9-yl)methyl]acetamide

The procedure is as in Example 19, starting from the compound obtainedin Preparation 39.

EXAMPLE 73N-[(5-Methoxy-6,7,8,9-tetrahydro-2-oxabenzo[cd]azulen-9-yl)methyl]propionamide

The procedure is as in Example 2, starting from the compound obtained inPreparation 40.

EXAMPLE 74 N-(7-Methoxy-1,2,3,4-tetrahydro-1-anthracenyl)acetamide

The procedure is as in Example 1, starting from the compound obtained inPreparation 41.

EXAMPLE 75 N-(6-Methoxy-1,2,3,4-tetrahydro-1-anthracenyl)acetamide

The procedure is as in Example 1, starting from the compound obtained inPreparation 42.

EXAMPLE 76N-(5,6,7,8-Tetrahydronaphtho[2,3-b]thiophen-5-yl)-1-cyclopropylcarboxamide

The procedure is as in Example 3, starting from the compound obtained inPreparation 43.

EXAMPLE 77N-(3-Ethyl-5,6,7,8-tetrahydronaphtho[2,3-b]thiophen-5-yl)heptanamide

The procedure is as in Example 14, starting from the compound obtainedin Preparation 44.

EXAMPLE 78 N-(6,7,8,9-Tetrahydronaphtho[1,2-b]thiophen-6-yl)acetamide

The procedure is as in Example 1, starting from the compound obtained inPreparation 45.

EXAMPLE 79 N-(6,7,8,9-Tetrahydronaphtho[1,2-b]thiophen-9-yl)acetamide

The procedure is as in Example 1, starting from the compound obtained inPreparation 46.

EXAMPLE 80N-(6,7,8,9-Tetrahydronaphtho[2,1-b]thiophen-9-yl)-1-cyclohexanecarboxamide

The procedure is as in Example 13, starting from the compound obtainedin Preparation 47.

EXAMPLE 81N-(6,7,8,9-Tetrahydronaphtho[2,1-b]thiophen-9-yl)-2,2,2-trifluoroacetamide

The procedure is as in Example 1, starting from the compound obtained inPreparation 47 and with replacement of the acetic anhydride withtrifluoroacetic anhydride.

EXAMPLE 82N-(1-Methoxy-6,7,8,9-tetrahydronaphtho[2-b]thiophen-9-yl)methyl]acetamide

The procedure is as in Example 1, starting from the compound obtained inPreparation 48.

EXAMPLE 83N-(1-Methoxy-6,7,8,9-tetrahydronaphtho[2,1-b]thiophen-9-yl)methyl]acetamide

The procedure is as in Example 2, starting from the compound obtained inPreparation 49.

EXAMPLE 84 N-[(3-Methoxy-2,3-dihydro-1H-1-phenalenyl)methyl]acetamide

The procedure is as in Example 1, starting from the compound obtained inPreparation 50.

EXAMPLE 85N-[3-(3,8-Dimethoxy-1,2-dihydro-1-acenaphthylenyl)propyl]-2,2,2-trifluoroacetamide

The procedure is as in Example 63, with acetyl chloride being condensedwith the compound obtained in Preparation 51.

EXAMPLE 86N-Pentyl-4-(3,8-dimethoxy-1,2-dihydro-1-acenaphthylenyl)butanamide

The procedure is as in Example 66, with N-pentylamine being condensedwith the acid chloride of the compound obtained in Preparation 52.

EXAMPLE 87 N-[(4-Methoxy-2,3-dihydro-1H-2-phenalenyl)methyl]acetamide

The procedure is as in Example 1, starting from the compound obtained inPreparation 53.

EXAMPLE 88N-[(4-Methoxy-2,3-dihydro-1H-2-phenalenyl)methyl]-1-cyclobutanecarboxamide

The procedure is as in Example 1, starting from the compound obtained inPreparation 53 and with replacement of the acetic anhydride withcyclobutanecarboxylic anhydride.

EXAMPLE 89N-[(4-Hydroxy-2,3-dihydro-1H-2-phenalenyl)methyl]-1-cyclobutanecarboxamide

The procedure is as in Example 6, starting from the compound obtained inExample 88.

EXAMPLE 90N-[(4-Benzyloxy-2,3-dihydro-1H-2-phenalenyl)methyl]-1-cyclobutanecarboxamide

The procedure is as in Example 7, starting from the compound obtained inExample 89.

EXAMPLE 91N-[(4-Allyfoxy-2,3-dihydro-1H-2-phenalenyl)methyl]-1-cyclobutanecarboxamide

The procedure is as in Example 8, starting from the compound obtained inExample 89.

EXAMPLE 92N-[(4-Methoxy-2,3-dihydro-1H-2-phenalenyl)methyl]ethanethioamide

The procedure is as in Example 24, starting from the compound obtainedin Example 87.

EXAMPLE 93 N-[(4-Ethyl-2,3-dihydro-1H-2-phenalenyl)methyl]propanamide

The procedure is as in Example 2, starting from the compound obtained inPreparation 54.

EXAMPLE 94N-Cyclopropyl-2-(4,9-dimethoxy-2,3-dihydro-1H-2-phenalenyl)acetamide

The procedure is as in Example 57, with N-cyclopropylamine beingcondensed with the acid chloride obtained in Preparation 55.

EXAMPLE 95 N-Methyl-4-methoxy-2,3-dihydro-1H-2-phenalenecarboxamide

The procedure is as in Example 57, with N-methylamine being condensedwith the acid chloride obtained in Preparation 56.

EXAMPLE 96 N-[2-(4-Methoxy-2,3-dihydro-1H-2-phenalenyl)ethyl]heptanamide

The procedure is as in Example 52, starting from the compound obtainedin Preparation 57.

EXAMPLE 97N-Methyl-N-[2-(4-methoxy-2,3-dihydro-1H-2-phenalenyl)ethyl]heptanamide

The procedure is as in Example 5, starting from the compound obtained inExample 96.

EXAMPLE 98 N-[3-(4-Methoxy-2,3-dihydro-1H-2-phenalenyl)propyl]acetamide

The procedure is as in Example 38, starting from the compound obtainedin Preparation 58.

EXAMPLE 99 N-[(6-Chloro-2,3-dihydro-1H-2-phenalenyl)methyl]acetamide

The procedure is as in Example 1, starting from the compound obtained inPreparation 59.

EXAMPLE 100N-[(1,6-Dimethoxy-7,8,9,10-tetrahydrocyclohepta[de]naphthalen-8-yl)methyl]acetamide

The procedure is as in Example 1, starting from the compound obtained inPreparation 60.

EXAMPLE 101N-[(1,6-Dimethoxy-7,8,9,10-tetrahydrocyclohepta[de]naphthalen-8-yl)methyl]-1-cyclopropanecarboxamide

The procedure is as in Example 3, starting from the compound obtained inPreparation 60.

EXAMPLE 102N-Ethyl-1,6-dimethoxy-7,8,9,10-tetrahydrocyclohepta[de]-naphthalene-8-carboxamide

The procedure is as in Example 57, with N-ethylamine being condensedwith the acid chloride obtained in Preparation 61.

EXAMPLE 103 N-(8-Methoxy-1,2-dihydro-1-acenaphthylenyl)acetamide

The procedure is as in Example 1, starting from the compound obtained inPreparation 62.

Melting point: 217-219° C.

The compounds of Examples 104 and 105 are obtained by the action of HBron the compound obtained in Example 84.

EXAMPLE 104 N-[(3-Hydroxy-2,3-dihydro-1H-1-phenalenyl)methyl]acetamideEXAMPLE 105 N-[(3-Bromo-2,3-dihydro-1H-1-phenalenyl)methyl]acetamideEXAMPLE 106 N-[(3-Oxo-2,3-dihydro-1H-1-phenalenyl)methyl]acetamide

The title compound is obtained by customary oxidation of the alcoholobtained in Example 104.

EXAMPLE 107 N-[(4-Methoxy-2,3-dihydro-1H-1-phenalenyl)methyl]butanamide

The amine obtained in Preparation 1 (400 mg, 1.76.10⁻³ mol, 1 eq.) isdiluted with anhydrous dichloromethane (12 ml) in the presence oftriethylamine (368 μl, 2.64.10⁻³ mol. 1.5 eq.). At 0° C., butanoylchloride (183 μl, 1.76.10⁻³ mol, 1 eq.) is added slowly. The reactionmixture is stirred at ambient temperature for 40 minutes. Afterseparation of the phases, washings of the organic phase with a saturatedNaHCO₃ solution, water and then a saturated NaCl solution, and dryingover MgSO₄ and finally evaporating off the solvent under reducedpressure, the residue is purified using flash chromatography (1. CH₂Cl₂;2. CH₂Cl₂/MeOH: 99/1). The title compound is obtained in the form of awhite solid by recrystallisation from a hexane/AcOEt mixture.

Melting point: 100° C.; Elemental microanalysis:

C H N % calculated 76.74 7.80 4.71 % found 76.65 7.89 4.67

EXAMPLE 108 N-[2-(9-Methoxy-2,3-dihydro-1H-1-phenalenyl)ethyl]acetamide

The nitrile obtained in Preparation 63 (219 mg, 9.23.104 mol), dissolvedin tetrahydrofuran (22 ml), is hydrogenated at ambient temperature inthe presence of acetic anhydride (174 μl, 1.85.10⁻³ mol, 2 eq.) andRaney nickel. After 4 hours' hydrogenation, the reaction mixture isfiltered over Celite, rinsed and evaporated under reduced pressure. Theresidue is then taken up in dichloromethane and washed with water, thenwith a saturated NaHCO₃ solution and subsequently with water. Afterdrying over MgSO₄ and evaporating off the solvent, the residue ispurified using flash chromatography (AcOEt/petroleum ether: 30/50) andrecrystallised from a cyclohexane/AcOEt mixture. The title product isisolated in the form of a white solid.

Melting point: 98° C.; Elemental microanalysis:

C H N % calculated 76.30 7.47 4.94 % found 76.13 7.60 4.79

EXAMPLE 109 N-[2-(9-Methoxy-2,3-dihydro-1H-1-phenalenyl)ethyl]butanamide

The procedure is as in Example 108, with replacement of the aceticanhydride with butyric anhydride. The title product is isolated in theform of an oil.

EXAMPLE 110 N-[2-(4-Methoxy-2,3-dihydro-1H-1-phenalenyl)ethyl]butanamide

In a 100 ml three-necked flask, the hydrochloride obtained inPreparation 19 (300 mg, 1.08.10⁻³ mol. 1 eq.) is solubilised in atwo-phase CH₂Cl₂/water medium (12 ml/12 ml) in the presence of sodiumcarbonate (801 mg, 7.56.10⁻³ mol, 7 eq.). Butanoyl chloride (112 μl,1.08.10mol, 1 eq.) is added at 0° C. The reaction mixture is stirred atambient temperature for 20 minutes. After separation of the phases,washing of the organic phase with a saturated NaHCO₃ solution, H₂O andthen a saturated NaCl solution, then drying over MgSO₄ and finallyevaporating off the solvent under reduced pressure, the residue ispurified using flash chromatography (1. CH₂Cl₂; 2. CH₂Cl₂/MeOH: 99/1).The title product is isolated in the form of an oil.

EXAMPLE 111N-[2-(4,9-Dimethoxy-2,3-dihydro-1H-1-phenalenyl)ethyl]propanamide

The procedure is as in Example 108, starting from the amine obtained inPreparation 64 and with replacement of the acetic anhydride withpropionic anhydride. The title product obtained is isolated in the formof a white solid.

Melting point: 111° C.; Elemental microanalysis:

C H N % calculated 73.37 7.70 4.28 % found 73.45 7.87 4.18

EXAMPLE 112N-[2-(4,9-Dimethoxy-2,3-dihydro-1H-1-phenalenyl)ethyl]butanamide

The procedure is as in Example 111, with replacement of the propionicanhydride with butyric anhydride. The title product obtained is isolatedin the form of a white solid.

Melting point: 99° C.; Elemental microanalysis:

C H N % calculated + ⅛H₂O 73.39 7.99 4.08 % found 73.12 8.16 3.97

EXAMPLE 113N-[2-(4,9-Dimethoxy-2,3-dihydro-1H-1-phenalenyl)ethyl]-1-cyclopropanecarboxamide

At 0° C., cyclopropanoyl chloride (67 μl, 7.37.10⁻³ mol, 1 eq.) is addedto a solution of the amine obtained in Preparation 64 (200 mg, 7.37.104mol, 1 eq.) in a dichloro-methane/water mixture (10 ml/10 ml) in thepresence of sodium carbonate (547mg, 5.16.10⁻³ mol, 7 eq.). The reactionmixture is stirred at ambient temperature for 15 minutes. Neutralisationis carried out by adding a few drops of ammonium hydroxide. Afterwashing with water, drying over MgSO₄ and then evaporating off thesolvent under reduced pressure, the residue is purified by flashchromatography (AcOEt/petroleum ether 40/60). The title product isisolated in the form of a white solid by recrystallisation from acyclohexane/AcOEt mixture.

Melting point: 120° C.; Elemental microanalysis:

C H N % calculated 74.31 7.42 4.13 % found 74.17 7.57 4.05

EXAMPLE 114N-[2-(4,9-Dimethoxy-2,3-dihydro-1H-1-phenalenyl)ethyl]acetamide

The procedure is as in Example 111, with replacement of the propionicanhydride with acetic anhydride. The title product is isolated in theform of a white solid.

Melting point: 125° C.; Elemental microanalysis:

C H N % calculated 72.82 7.40 4.47 % found 72.68 7.60 4.35

EXAMPLE 115 N-[2-(9-Methoxy-2,3-dihydro-1H-1-phenalenyl)methyl]acetamide

In a 50 ml three-necked flask, the amine obtained in Preparation 65 (172mg, 7.57.10 mol, 1 eq.) is solubilised in a two-phase CH₂Cl₂/watermedium (9 ml/9 ml) in the presence of sodium carbonate (561 mg,5.30.10⁻³ mol, 7 eq.). Acetic anhydride (72 μl, 7.57.10⁻³ mol, 1 eq.) isadded at 0° C. The reaction mixture is stirred at ambient temperaturefor 20 minutes. After separation of the phases, washings of the organicphase with a saturated NaHCO₃ solution, H20 and a saturated NaClsolution, then drying over MgSO₄ and finally evaporating off the solventunder reduced pressure, the residue (180 mg) is purified using flashchromatography (AcOEt/petroleum ether, 40/60). The title product isisolated in the form of a white solid by recrystallisation from acyclohexane/AcOEt mixture.

Melting point: 192° C.; Elemental microanalysis:

C H N % calculated 75.81 7.11 5.20 % found 75.43 7.35 5.12

EXAMPLE 116N-[2-(9-Methoxy-2,3-dihydro-1H-1-phenalenyl)methyl]butanamide

The procedure is as in Example 115, with replacement of the aceticanhydride with butanoyl chloride. The title product is isolated in theform of a white solid.

Melting point:114° C.; Elemental microanalysis:

C H N % calculated 76.74 7.80 4.71 % found 76.52 8.02 4.55

EXAMPLE 117N-[2-(4,9-Dimethoxy-2,3-dihydro-1H-1-phenalenyl)methyl]acetamide

The procedure is as in Example 115, starting from the amine obtained inPreparation 3. The title product is isolated in the form of a whitesolid.

Melting point: 184° C.; Elemental microanalysis:

C H N % calculated 72.22 7.07 4.68 % found 71.85 7.30 4.52

EXAMPLE 118N-[2-(4,9-Dimethoxy-2,3-dihydro-1H-1-phenalenyl)methyl]propanamide

The procedure is as in Example 117, with replacement of the aceticanhydride with propanoyl chloride. The title product is isolated in theform of a white solid.

Melting point: 158° C.; Elemental microanalysis:

C H N % calculated 72.82 7.40 4.47 % found 72.61 7.55 4.39

EXAMPLE 119N-[2-(4,9-Dimethoxy-2,3-dihydro-1H-1-phenalenyl)methyl]butanamide

The procedure is as in Example 117, with replacement of the aceticanhydride with butanoyl chloride. The title product is isolated in theform of a white solid.

Melting point: 140° C.; Elemental microanalysis:

C H N % calculated 73.37 7.70 4.23 % found 73.15 7.80 4.14

Separation of the two enantiomers is carried out on a chiral column:[α]_(D) (589 nm, T=23° C.) F enantiomer 1=−22°+2 (CHCl₃, 5 mg/ml)enantiomer 2=+20°+2 (CHCl₃, 5 mg/ml)

EXAMPLE 120N-[2-(4,9-Dimethoxy-2,3-dihydro-1H-1-phenalenyl)methyl]-1-cyclopropanecarboxamide

The procedure is as in Example 117, with replacement of the aceticanhydride with cyclopropanoyl chloride. The title product is isolated inthe form of a white solid.

Melting point: 192° C.; Elemental microanalysis:

C H N % calculated 73.82 7.12 4.30 % found 73.62 7.27 4.18

EXAMPLE 121(E)-N-Methyl-2-(4-methoxy-2,3-dihydro-1H-1-phenalenylidene)acetamide

The acid obtained in Preparation 66 (250 mg, 9.84.10⁻⁴ mol, 1 eq.) issolubilised in anhydrous dichloromethane (20 ml). At 0° C., under argon,triethylamine on potassium hydroxide (164 μl, 1.18.10⁻³ mol, 1.2 eq.) isadded, followed by isobutyl chloroformate (153 μl, 1.18.10⁻³ mol, 1.2eq.). Complete formation of the anhydride starting from the acid iscarried out at 0° C. in 1 hour 10 minutes. Separately, methylaminehydrochloride (199 mg, 2.95.10⁻³ mol, 3 eq.) is stirred under argontogether with anhydrous dichloromethane (18 ml) and triethylamine (411μl, 2.95.10⁻³ mol, 3 eq.). After 10 minutes' stirring, the resultingsuspension is added to the reaction mixture and stirring is continuedfor one night at ambient temperature. After one washing with water anddrying over magnesium sulphate, the filtrate is evaporated to drynessunder reduced pressure. Purification on a silica gel column(dichloromethane/methanol, 98/2) followed by recrystallisation from anAcOEt/cyclohexane mixture allows the title product to be isolated in theform of a beige solid.

Melting point: 174° C.; Elemental microanalysis:

C H N % calculated 76.38 6.41 5.24 % found 76.10 6.39 5.18

EXAMPLE 122(Z)-N-Methyl-2-(4-methoxy-2,3-dihydro-1H-1-phenalenylidene)acetamide

The procedure is as in Example 121, starting from the acid obtained inPreparation 67.

Melting point: 175° C.; Elemental microanalysis:

C H N % calculated + ⅛H₂O 75.74 6.45 5.20 % found 75.72 6.55 5.06

EXAMPLE 123 N-(1,2-Dihydro-1-acenaphthylenylmethyl)acetamide

In a 100 ml three-necked flask, the hydrochloride obtained inPreparation 68 (550 mg, 2.50.10⁻³ mol, 1 eq.) is solubilised in atwo-phase CH₂Cl₂/water medium (20 ml/20 ml) in the presence of sodiumcarbonate (1.86 g, 1.75.10⁻² mol, 7 eq.). Acetic anhydride (236 μl,2.50.10⁻³ mol, 1 eq.) is added at 0° C. The reaction mixture is stirredat ambient temperature for 20 minutes. After separation of the phases,washings of the organic phase with a saturated NaHCO₃ solution, H₂O anda saturated NaCl solution, then drying over MgSO₄ and finallyevaporating off the solvent under reduced pressure, the residue having aweight of 500 mg is purified using flash chromatography (1. CH₂Cl₂; 2.CH₂Cl₂/MeOH: 99/1).

The title product is isolated in the form of a white solid byrecrystallisation from a cyclohexane/AcOEt mixture.

Melting point: 145° C.; Elemental microanalysis:

C H N % calculated 79.97 6.71 6.22 % found 79.83 6.82 6.15

EXAMPLE 124 N-(1,2-Dihydro-1-acenaphthylenylmethyl)propanamide

The procedure is as in Example 123, with replacement of the aceticanhydride with propionic anhydride. The title product is isolated in theform of a white solid.

Melting point 111° C. Elemental microanalysis:

C H N % calculated 80.30 7.16 5.85 % found 80.15 7.28 5.70

EXAMPLE 125 N-(1,2-Dihydro-1-acenaphthylenylmethyl)butanamide

The procedure is as in Example 123, with replacement of the aceticanhydride with butanoyl chloride. The title product is isolated in theform of a white solid.

Melting point: 111° C.; Elemental microanalysis:

C H N % calculated 80.57 7.56 5.53 % found 80.02 7.70 5.40

EXAMPLE 126N-(1,2-Dihydro-1-acenaphthylenylmethyl)-1-cyclopropanecarboxamide

The procedure is as in Example 123, with replacement of the aceticanhydride with cyclopropanoyl chloride.

Melting point: 146° C.; Elemental microanalysis:

C H N % calculated 81.24 6.82 5.57 % found 81.13 6.88 5.52

EXAMPLE 127 N-(8-Methoxy-1,2-dihydro-1-acenaphthylmethyl)acetamide

In a 100 ml three-necked flask, the amine obtained in Preparation 69(385 mg, 1.81.10⁻³ mol, 1 eq.) is solubilised in a two-phaseCH₂Cl₂/water medium (20 ml/20 ml) in the presence of sodium carbonate(1.34 g, 1.26.10⁻² mol, 7 eq.). Acetic anhydride (170 μl, 1.81.10⁻³ mol,1 eq.) is added at 0° C. The reaction mixture is stirred at ambienttemperature for 40 minutes. After separation of the phases, washing ofthe organic phase with a saturated NaHCO₃ solution, H₂O and a saturatedNaCl solution, then drying over MgSO₄ and finally evaporating off thesolvent under reduced pressure, the residue having a weight of 360 mg ispurified using flash chromatography (1. CH₂Cl₂; 2. CH₂Cl₂/MeOH: 99/1).The title product is isolated in the form of a white solid byrecrystallisation from a cyclohexane/AcOEt mixture.

Melting point: 148° C.; Elemental microanalysis:

C H N % calculated + ½H₂O 72.70 6.86 5.30 % found 72.08 6.86 5.24

EXAMPLE 128 N-(8-Methoxy-1,2-dihydro-1-acenaphthylmethyl)propanamide

The procedure is as in Example 127, with replacement of the aceticanhydride with propionic anhydride.

Melting point: 160° C.; Elemental microanalysis:

C H N % calculated + ½H₂O 73.35 7.24 5.03 % found 73.88 7.25 5.15

EXAMPLE 129N-(8-Methoxy-1,2-dihydro-1-acenaphthylmethyl)-1-cyclopropanecarboxamide

The procedure is as in Example 127, with replacement of the aceticanhydride with cyclopropanoyl chloride.

Melting point: 185° C.; Elemental microanalysis:

C H N % calculated + ¼H₂O 75.63 6.88 4.90 % found 75.78 6.98 4.93

EXAMPLE 130 N-(8-Methoxy-1,2-dihydro-1-acenaphthylmethyl)butanamide

The procedure is as in Example 127, with replacement of the aceticanhydride with butanoyl chloride. The title product is obtained in theform of a white solid.

Melting point: 146° C.; Elemental microanalysis:

C H N % calculated 76.30 7.47 4.94 % found 76.12 7.51 4.93

The two enantiomers are separated on a chiral column:$\lbrack\alpha\rbrack_{D}\left( {{589\quad {nm}},\quad {T = {23{^\circ}\quad {C.}}}} \right)\left\{ \begin{matrix}{{{enantiomer}\quad 1} = {{{- 20}{^\circ}} \pm {2\left( {{CHCl}_{3},\quad {5\quad {mg}\text{/}{ml}}} \right)}}} \\{{{enantiomer}\quad 2} = {{{+ 18}{^\circ}} \pm {2\left( {{CHCl}_{3},\quad {5\quad {mg}\text{/}{ml}}} \right)}}}\end{matrix} \right.$

EXAMPLE 131 N-[2-(1,2-Dihydro-1-acenaphthyl)ethyl]acetamide

The nitrile obtained in Step B of Preparation 70 (230 mg, 1.20.10⁻³mol), diluted with tetrahydrofuran (25 ml), is hydrogenated at ambienttemperature in the presence of acetic anhydride (200 μl, 2.12.10⁻³ mol,1.8 eq.) and Raney nickel. After 5 hours' hydrogenation, the reactionmixture is filtered over Celite, rinsed and evaporated under reducedpressure. The residue is then taken up in dichloromethane and washedwith water, then with a saturated NaHCO₃ solution and subsequently withwater. After drying over MgSO₄ and evaporating off the solvent, theresidue is purified by flash chromatography (CH₂Cl₂/methanol: 99/1).

Melting point: 116° C.; Elemental microanalysis:

C H N % calculated 80.30 7.10 5.85 % found 80.11 7.23 5.89

EXAMPLE 132 N-[2-(1,2-Dihydro-1-acenaphthyl)ethyl]propanamide

The procedure is as in Example 131, with replacement of the aceticanhydride with propionic anhydride.

Melting point: 100° C.; Elemental microanalysis:

C H N % calculated 80.57 7.56 5.53 % found 80.34 7.54 5.50

EXAMPLE 133 N-[2-(1,2-Dihydro-1-acenaphthyl)ethyl]butanamide

The procedure is as in Example 131, with replacement of the aceticanhydride with butyric anhydride. The title product is isolated in theform of a white solid.

Melting point: 98° C.; Elemental microanalysis:

C H N % calculated 80.86 7.92 5.24 % found 80.86 7.96 5.21

EXAMPLE 134N-[2-(1,2-Dihydro-1-acenaphthyl)ethyl]cyclopropanecarboxamide

At 0° C., under argon, the amine obtained in Preparation 70 (500 mg,2.53.10⁻³ mol, 1 eq.) is solubilised in anhydrous dichloromethane (17ml) in the presence of triethylamine (530 μl, 3.80.10⁻³ mol, 1.5 eq.).Cyclopropanoyl chloride (230 μl, 2.53.10⁻³ mol 1 eq.) is added dropwiseat 0° C. The reaction mixture is stirred at ambient temperature for 20minutes. After washings with water and with a saturated NaCl solution,and drying over MgSO₄ and then evaporating off the solvent under reducedpressure, the residue is recrystallised from a cyclohexane/AcOEtmixture.

Melting point: 159° C.;

EXAMPLE 135 N-[2-(8-Methoxy-1,2-dihydro-1-acenaphthyl)ethyl]acetamide

The procedure is as in Example 131, starting from the nitrile obtainedin Step A of Preparation 71. The title product is isolated in the formof a white solid.

Melting point: 118° C.; Elemental microanalysis:

C H N % calculated 80.30 7.10 5.85 % found 80.11 7.23 5.89

EXAMPLE 136 N-[2-(8-Methoxy-1,2-dihydro-1-acenaphthyl)ethyl]propanamide

The procedure is as in Example 135, with replacement of the aceticanhydride with propionic anhydride.

Melting point: 100° C.; Elemental microanalysis:

C H N % calculated 80.57 7.56 5.53 % found 80.34 7.54 5.50

EXAMPLE 137 N-[2-(8-Methoxy-1,2-dihydro-1-acenaphthyl)ethyl]butanamide

The procedure is as in Example 135, with replacement of the aceticanhydride with butyric anhydride.

Melting point: 98° C.; Elemental microanalysis:

C H N % calculated 80.86 7.92 5.24 % found 80.86 7.96 5.21

EXAMPLE 138N-[2-(8-Methoxy-1,2-dihydro-1-acenaphthyl)ethyl]-1-cyclopropanecarboxamide

The procedure is as in Example 134, starting from the amine obtained inPreparation 71.

Melting point: 159° C.;

EXAMPLE 139N-[2-(1-Methoxy-7,8,9,10-tetrahydrocyclohepta[de]naphthalen-7-ylidene)ethyl]propanamide

The nitrile obtained in Preparation 72 (465 mg, 1.87.10⁻³ mol), dilutedwith tetrahydrofuran (25 ml), is hydrogenated at ambient temperature inthe presence of propionic anhydride (480 μl, 3.74.10⁻³ mol, 2 eq.) andRaney nickel. After 24 hours' hydrogenation, the reaction mixture isfiltered over Celite, rinsed and evaporated under reduced pressure. Theresidue is then taken up in dichloromethane and washed with water, thenwith a saturated NaHCO₃ solution and subsequently with water. Afterdrying over MgSO₄ and evaporating off the solvent, the residue ispurified using flash chromatography (1. CH₂Cl₂; 2. CH₂Cl₂/MeOH: 99/1).The title product is isolated in the form of a white solid.

E isomer:

The E isomer is obtained in the pure form by recrystallisation of thesolid obtained above, which corresponds to the E/Z mixture, from anAcOEt/cyclohexane mixture.

Melting point: 131° C.; Elemental microanalysis:

C H N % calculated 77.64 7.49 4.53 % found 77.28 7.54 4.36

PHARMACOLOGICAL STUDY EXAMPLE A Acute Toxicity Study

Acute toxicity was evaluated after oral administration to groups eachcomprising 8 mice (26±2 grams). The animals were observed at regularintervals during the course of the first day, and daily for the twoweeks following treatment. The LD₅₀ (dose that causes the death of 50%of the animals) was evaluated and demonstrated the low toxicity of thecompounds of the invention.

EXAMPLE B Melatonin Receptor Binding Study on Pars Tuberalis Cells ofSheep

Melatonin receptor binding studies of the compounds of the inventionwere carried out according to conventional techniques on pars tuberaliscells of sheep, the pars tuberalis of to the adenohypophysis beingcharacterised in mammals by a high density of melatonin receptors(Journal of Neuroendocrinology, 1, pp 1-4, 1989).

Protocol

1) Sheep pars tuberalis membranes are prepared and used as target tissuein saturation experiments to determine the binding capacities andaffinities for 2-[¹²⁵I]-iodomelatonin.

2) Sheep pars tuberalis membranes are used as target tissue incompetitive binding experiments using the various test compounds incomparison with melatonin. Each experiment is carried out in triplicateand a range of different concentrations is tested for each compound. Theresults, after statistical processing, enable the binding affinities ofthe compound tested to be determined.

Results

The compounds of the invention appear to have a strong affinity formelatonin receptors.

EXAMPLE C Melatonin mt₁ and MT₂ Receptor Binding Study

The mt₁ or MT₂ receptor binding experiments are carried out using2-[¹²⁵I]-melatonin as reference radioligand. The radioactivity retainedis determined using a Beckman® LS 6000 liquid scintillation counter.

Competitive binding experiments are then carried out in triplicate usingthe various test compounds. A range of different concentrations istested for each compound. The results enable the binding affinities ofthe compounds tested (IC₅₀) to be determined.

The IC₅₀ values found for the compounds of the invention show that thebinding of the compounds tested is very strong for one or other of themt₁ and MT₂ receptor sub-types, the values being in a range from 0.1 to10 nM.

EXAMPLE D Four Plate Test

The products of the invention are administered by the oesophageal routeto groups each comprising ten mice. One group is given syrup of gum.Thirty minutes after administration of the products to be studied, theanimals are placed in cages in which the floor is composed of four metalplates. Each time the animal passes from one plate to another itreceives a light electric shock (0.35 mA). The number of passages fromone plate to another in one minute is recorded. After administration,the compounds of the invention significantly increase the number ofpassages from one plate to another, demonstrating the anxiolyticactivity of the compounds of the invention.

EXAMPLE E Action of the Compounds of the Invention on the CircadianRhythms of Locomotive Activity of the Rat

The involvement of melatonin in influencing, by day/night alternation,the majority of physiological, biochemical and behavioural circadianrhythms has made it possible to establish a pharmacological model forresearch into melatoninergic ligands.

The effects of the molecules are tested in relation to numerousparameters and, in particular, in relation to the circadian rhythms oflocomotive activity, which represent a reliable marker of the activityof the endogenous circadian clock. In this study, the effects of suchmolecules on a particular experimental model, namely the rat placed intemporal isolation (permanent darkness), are evaluated.

Experimental Protocol

One-month-old Long Evans male rats are subjected, as soon as they arriveat the laboratory, to a light cycle of 12 hours of light per 24 hours(LD 12: 12). After 2 to 3 weeks' adaptation, they are placed in cagesfitted with a wheel connected to a recording system in order to detectthe phases of locomotive activity and thus monitor the nychthemeral (LD)or circadian (DD) rhythms.

As soon as the rhythms recorded show a stable pattern in the light cycleLD 12: 12, the rats are placed in permanent darkness (DD).

Two to three weeks later, when the free course (rhythm reflecting thatof the endogenous clock) is clearly established, the rats are given adaily administration of the molecule to be tested.

The observations are made by means of visualisation of the rhythms ofactivity:

influence on the rhythms of activity by the light rhythm,

disappearance of the influence on the rhythms in permanent darkness,

influence by the daily administration of the molecule; transitory orlong-lasting effect.

A software package makes it possible:

to measure the duration and intensity of the activity, the period of therhythm of the animals during free course and during treatment,

possibly to demonstrate by spectral analysis the existence of circadianand non-circadian (for example ultradian) components.

Results:

The compounds of the invention clearly appear to allow powerful actionon the circadian rhythm via the melatoninergic system.

EXAMPLE F Anti-arrhythmic Activity

Protocol

(Ref: LAWSON J. W. et al. J. Pharmacol. Expert. Therap., 1968, 160, pp22-31)

The test substance is administered intraperitoneally to a group of 3mice 30 minutes before they are subjected to anaesthesia withchloroform. The animals are then observed for 15 minutes. The absence ofrecording of arrhythmia and of cardiac frequencies higher than 200beats/min (control: 400-480 beats/min) in at least two animals indicatessignificant protection.

EXAMPLE G Pharmaceutical Composition: Tablets

1000 tablets each comprising 5 mg of [(4-methoxy-2,3-dihydro- 5 g1H-phenalenyl)-methyl]propionamide (Example 2) wheat starch 20 g  maizestarch 20 g  lactose 30 g  magnesium stearate 2 g silica 1 ghydroxypropyl cellulose 2 g

We claim:
 1. A compound of formula (I):

wherein: A forms with the group to which it is bonded a tricyclic systemselected from A₁, A₂, A₃ and A₄:

R¹ represents hydrogen, halogen or linear or branched (C₁-C₆)alkyl,linear or branched (C₁-C₆)alkoxy, hydroxy or oxo, R² and R³, which maybe the same or different, represent halogen or R_(a), OR_(a), COR_(a),OCOR_(a) or COOR_(a) (wherein R_(a) represents hydrogen, optionallysubstituted linear or branched (C₁-C₆)alkyl, linear or branched(C₁-C₆)trihaloalkyl, optionally substituted linear or branched(C₂-C₆)alkenyl, optionally substituted linear or branched(C₂-C₆)alkynyl, optionally substituted (C₃-C₈)-cycloalkyl, optionallysubstituted (C₃-C₈)cycloalkyl-(C₁-C₆)alkyl in which the alkyl moiety islinear or branched, or optionally substituted aryl), the symbols(R²)_(m) and (R³)_(m′) denote that the ring in question may besubstituted by from 1 to 3 groups (which may be the same or different)belonging to the definitions for R² and R³, X, when A represents atricyclic system A₁, A₂, A₃ or A₄, represents sulphur, (CH₂)_(q)(wherein q is 1 or 2), —CH═CH—, or NR⁴ (wherein R⁴ represents hydrogenor optionally substituted linear or branched (C₁-C₆)alkyl), or Xrepresents oxygen when A represents the tricyclic system A₁, n is aninteger such that 0≦n≦3 p is an integer such that 1≦p≦3 when n is 1, 2or 3 and the

 chain is in the b position and A represents either A₂, A₃ or A₄ whereinX represents —CH═CH—, or A₁,  and such that 0≦p≦3 in all other cases, it being possible for the

 chain to be unsubstituted or substituted by one or more groups, whichmay be the same or different, selected from R_(a), OR_(a), COR_(a),COOR_(a) or halogen, B represents:

 wherein R_(a) is as defined hereinbefore, Z represents oxygen orsulphur,  and R⁵ represents R_(a) or NR⁶R⁷ wherein R⁶ and R⁷, which maybe the same or different, represent R_(a), or

 wherein Z, R⁶ and R⁷ are as defined hereinbefore, the symbol denotesthat the bond may be single or double provided that the valency of theatoms is respected,  it being understood that the symbol

 is used to denote the formula

 (in which case p is other than 0),  with the proviso that: when thetricyclic group of formula A₁ is a 6-methoxytetrahydrobenzo[cd]indole, Bcannot represent NHCOMe, the compound of formula (I) cannot representN-(4-methyl-2,3-dihydro-1H-1-phenalenyl)-1-cyclopropanecarboxamide,N-(4-methyl-2,3-dihydro-1H-1-phenalenyl)-2-chloroacetamide,2-methyl-1,3,4,5-tetrahydrobenzo[cd]indole-3-carboxamide,N-(5-hydroxy-1,2,2a,3,4,5-hexahydro-4-acenaphthylenyl)acetamide,N-(5-hydroxy-1,2,2a,3,4,5-hexahydro-4-acenaphthylenyl)benzamide orN-(1,2,2a,3,4,5-hexahydro-4-acenaphthylenyl)acetamide,  it beingunderstood that: “aryl” is used to denote phenyl or naphthyl eachoptionally substituted by one or more groups, which may be the same ordifferent, selected from hydroxy, linear or branched (C₁-C₆)alkoxy,linear or branched (C₁-C₆)alkyl, cyano, nitro, amino, trihaloalkyl, orhalogen, the expression “optionally substituted” applied to the terms“alkyl”, “alkenyl” and “alkynyl” denotes that those groups may besubstituted by one or more groups, which may be the same or different,selected from hydroxy, linear or branched (C₁-C₆)-alkoxy, aryl, orhalogen, the expression “optionally substituted” applied to the terms“cycloalkyl” and “cycloalkylalkyl” denotes that the cyclic moiety may besubstituted by one or more groups, which may be the same or different,selected from hydroxy, linear or branched (C₁-C₆)alkoxy, oxo, orhalogen, their enantiomers and diastereoisomers, and addition saltsthereof with a pharmaceutically acceptable acid or base.
 2. A compoundof formula (I) according to claim 1 represented by formula (I_(A)):

wherein: A forms with the group to which it is bonded a tricyclic systemselected from A′₁, A′₂, A′₃ and A′₄:

R¹ represents hydrogen, halogen or linear or branched (C₁-C₆)alkyl,linear or branched (C₁-C₆)alkoxy, hydroxy or oxo, R² and R³, which maybe the same or different, represent halogen or R_(a), OR_(a), COR_(a),OCOR_(a) or COOR_(a) (wherein R_(a) represents hydrogen, optionallysubstituted linear or branched (C₁-C₆)alkyl, linear or branched(C₁-C₆)trihaloalkyl, an optionally substituted linear or branched(C₂-C₆)alkenyl, optionally substituted linear or branched(C₂-C₆)alkynyl, optionally substituted (C₃-C₈)cycloalkyl, optionallysubstituted (C₃-C₈)cycloalkyl-(C₁-C₆)alkyl in which the alkyl moiety islinear or branched, or optionally substituted aryl), the symbols(R²)_(m) and (R³)_(m′) denote that the ring in question may besubstituted by from 1 to 3 groups (which may be the same or different)belonging to the definitions for R² and R³, X, when A represents atricyclic system A′₁, A′₂, A′₃ or A′₄, represents sulphur, (CH₂)_(q)(wherein q is 1 or 2), —CH═CH—, or NR⁴ (wherein R⁴ represents hydrogenor optionally substituted linear or branched (C₁-C₆)alkyl), or Xrepresents oxygen when A represents the tricyclic system A′₁, n is aninteger such that 0≦n≦3 p is an integer such that 1≦p≦3 when n is 1, 2or 3 and the —(CH₂)_(p)—B chain is in the b position and A representseither a group A′₂, A′₃ or A′₄ wherein X represents —CH═CH, or A′₁, andsuch that 0≦p≦3 in all other cases, it being possible for the (CH₂)_(p)chain to be unsubstituted or substituted by one or more groups, whichmay be the same or different, selected from R_(a), OR_(a), COR_(a),COOR_(a) or halogen, B represents:

 wherein R_(a) is as defined hereinbefore, Z represents oxygen orsulphur,  and R⁵ represents R_(a) or NR⁶R⁷ wherein R⁶ and R⁷, which maybe the same or different, represent R_(a), or

 wherein Z, R⁶ and R⁷ are as defined hereinbefore, the symbols denotesthat the bond may be single or double provided that the valency of theatoms is respected,  with the proviso that: when the tricyclic group offormula A′₁ is a 6-methoxytetrahydrobenzo[cd]indole, B cannot representNHCOMe, the compound of formula (I) cannot representN-(4-methyl-2,3-dihydro-1H-1-phenalenyl)-1-cyclopropanecarboxamide,N-(4-methyl-2,3-dihydro-1H-1-phenalenyl)-2-chloroacetamide,2-methyl-1,3,4,5-tetrahydrobenzo[cd]indole-3-carboxiamide,N-(5-hydroxy-1,2,2a,3,4,5-hexahydro-4-acenaphthylenyl)acetamide,N-(5-hydroxy-1,2,2a,3,4,5-hexahydro-4-acenaphthylenyl)benzamide orN-(1,2,2a,3,4,5-hexahydro-4-acenaphthylenyl)acetamide,  it beingunderstood that: “aryl” is used to denote phenyl or naphthyl eachoptionally substituted by one or more groups, which may be the same ordifferent, selected from hydroxy, linear or branched (C₁-C₆)alkoxy,linear or branched (C₁-C₆)alkyl, cyano, nitro, amino, trihaloalkyl, orhalogen, the expression “optionally substituted” applied to the terms“alkyl”, “alkenyl” and “alkynyl” denotes that those groups may besubstituted by one or more groups, which may be the same or different,selected from hydroxy, linear or branched (C₁-C₆)-alkoxy, aryl, orhalogen, the expression “optionally substituted” applied to the terms“cycloalkyl” and “cycloalkylalkyl” denotes that the cyclic moiety may besubstituted by one or more groups, which may be the same or different,selected from hydroxy, linear or branched (C₁-C₆)alkoxy, oxo, orhalogen, their enantiomers and diastereoisomers, and addition saltsthereof with a pharmaceutically acceptable acid or base.
 3. A compoundof formula (I) according to claim 1 represented by formula (I_(B)):

wherein: A forms with the group to which it is bonded a tricyclic systemselected from A″₁, A″₂, A″₃ and A″₄:

R¹ represents hydrogen, halogen or linear or branched (C₁-C₆)alkyl,linear or branched (C₁-C₆)alkoxy, hydroxy or oxo, R² and R³, which maybe the same or different, represent halogen or R_(a), OR_(a), COR_(a),OCOR_(a) or COOR_(a) (wherein R_(a) represents hydrogen, optionallysubstituted linear or branched (C₁-C₆)alkyl, linear or branched(C₁-C₆)trihaloalkyl, optionally substituted linear or branched(C₂-C₆)alkenyl, optionally substituted linear or branched(C₂-C₆)alkynyl, optionally substituted (C₃-C₈)cycloalkyl, optionallysubstituted (C₃-C₈)cycloalkyl-(C₁-C₆)alkyl in which the alkyl moiety islinear or branched, or optionally substituted aryl), the symbols(R²)_(m) and (R³)_(m)′ denote that the ring in question may besubstituted by from 1 to 3 groups (which may be the same or different)belonging to the definitions for R² and R³, X, when A represents atricyclic system A″₁, A″₂, A″₃ or A″₄, represents sulphur, (CH₂)_(q)(wherein q is 1 or 2), —CH═CH—, or NR⁴ (wherein R⁴ represents hydrogenor optionally substituted linear or branched (C₁-C₆)alkyl), or Xrepresents oxygen when A represents the tricyclic system A″₁, n is aninteger such that 0≦n≦3 p is an integer such that 1≦p≦3 it beingpossible for the

 chain to be unsubstituted or substituted by one or more groups, whichmay be the same or different, selected from R_(a), OR_(a), COR_(a),COOR_(a) or halogen, B represents:

 wherein R_(a) is as defined hereinbefore, Z represents oxygen orsulphur,  and R⁵ represents R_(a) or NR⁶R⁷  wherein R⁶ and R⁷, which maybe the same or different, represent R_(a), or

 wherein Z, R⁶ and R⁷ are as defined hereinbefore, the symbol denotesthat the bond may be single or double provided that the valency of theatoms is respected,  it being understood that: “aryl” is used to denotephenyl or naphthyl each optionally substituted by one or more groups,which may be the same or different, selected from hydroxy, linear orbranched (C₁-C₆)alkoxy, linear or branched (C₁-C₆)alkyl, cyano, nitro,amino, trihaloalkyl, or halogen, the expression “optionally substituted”applied to the terms “alkyl”, “alkenyl” and “alkynyl” denotes that thosegroups may be substituted by one or more groups, which may be the sameor different, selected from hydroxy, linear or branched (C₁-C₆)-alkoxy,aryl, or halogen, the expression “optionally substituted” applied to theterms “cycloalkyl” and “cycloalkylalkyl” denotes that the cyclic moietymay be substituted by one or more groups, which may be the same ordifferent, selected from hydroxy, linear or branched (C₁-C₆)alkoxy, oxo,or halogen, their enantiomers and diastereoisomers, and addition saltsthereof with a pharmaceutically acceptable acid or base.
 4. A compoundof formula (I) according to claim 1 wherein A forms with the groups towhich it is bonded a tricyclic system of formula A₁, their enantiomersand diastereoisomers, and addition salts thereof with a pharmaceuticallyacceptable acid or base.
 5. A compound of formula (I) according to claim1 wherein A forms with the groups to which it is bonded a tricyclicsystem of formula A₂, A₃ or A₄, their enantiomers and diastereoisomers,and addition salts thereof with a pharmaceutically acceptable acid orbase.
 6. A compound of formula (I) according to claim 1 wherein A formswith the group to which it is bonded a tricyclic system of formula A₁wherein X represents (CH₂)_(q) or —CH═CH—, their enantiomers anddiastereoisomers, and addition salts thereof with a pharmaceuticallyacceptable acid or base.
 7. A compound of formula (I) according to claim1 wherein A forms with the group to which it is bonded a tricyclicsystem of formula A₁ wherein X represents oxygen, their enantiomers anddiastereoisomers, and addition salts thereof with a pharmaceuticallyacceptable acid or base.
 8. A compound of formula (I) according to claim1 wherein A forms with the group to which it is bonded a tricyclicsystem of formula A₁ wherein X represents sulphur, their enantiomers anddiastereoisomers, and addition salts thereof with a pharmaceuticallyacceptable acid or base.
 9. A compound of formula (I) according to claim1 wherein A forms with the group to which it is bonded a tricyclicsystem of formula A₁ wherein X represents NR⁴, their enantiomers anddiastereoisomers, and addition salts thereof with a pharmaceuticallyacceptable acid or base.
 10. A compound of formula (I) according toclaim 1 wherein n represents an integer 0, 1 or 2, their enantiomers anddiastereoisomers, and addition salts thereof with a pharmaceuticallyacceptable acid or base.
 11. A compound of formula (I) according toclaim 1 wherein A forms with the groups to which it is bonded atricyclic system of formula A₁ wherein n is 0, 1 or 2, their enantiomersand diastereoisomers, and addition salts thereof with a pharmaceuticallyacceptable acid or base.
 12. A compound of formula (I) according toclaim 1 wherein A forms with the group to which it is bonded a2,3-dihydrophenalene, 1,2-dihydroacenaphthylene or7,8,9,10-tetrahydrocyclohepta[de]naphthalene tricyclic system, theirenantiomers and diastereoisomers, and addition salts thereof with apharmaceutically acceptable acid or base.
 13. A compound of formula (I)according to claim 1 wherein p represents an integer 0, 1 or 2, theirenantiomers and diastereoisomers, and addition salts thereof with apharmaceutically acceptable acid or base.
 14. A compound of formula (I)according to claim 1 wherein R² and R³, which may be the same ordifferent, represent an alkoxy or alkyl group or hydrogen, theirenantiomers and diastereoisomers, and addition salts thereof with apharmaceutically acceptable acid or base.
 15. A compound of formula (I)according to claim 1 wherein R¹ represents hydrogen, their enantiomersand diastereoisomers, and addition salts thereof with a pharmaceuticallyacceptable acid or base.
 16. A compound of formula (I) according toclaim 1 wherein the

chain is in the a or c position, their enantiomers and diastereoisomers,and addition salts thereof with a pharmaceutically acceptable acid orbase.
 17. A compound of formula (I) according to claim 1 wherein the

chain is in the a or c position and p represents an integer 0 (in whichcase the bond is single), 1 or 2, their enantiomers anddiastereoisomers, and addition salts thereof with a pharmaceuticallyacceptable acid or base.
 18. A compound of formula (I) according toclaim 1 wherein B represents NHCOR⁵, their enantiomers anddiastereoisomers, and addition salts thereof with a pharmaceuticallyacceptable acid or base.
 19. A compound of formula (I) according toclaim 1 wherein B represents CONHR⁶, their enantiomers anddiastereoisomers, and addition salts thereof with a pharmaceuticallyacceptable acid or base.
 20. A compound of formula (I) according toclaim 1 wherein A forms with the group to which it is bonded a2,3-dihydrophenalene, 1,2-dihydroacenaphthylene or7,8,9,10-tetrahydrocyclohepta[de]naphthalene tricyclic system, eachunsubstituted or substituted on the naphthalene moiety by one or morealkoxy or alkyl groups, and substituted in the a or c position by

wherein B represents NHCOR⁵ or CONHR⁶ group, their enantiomers anddiastereoisomers, and addition salts thereof with a pharmaceuticallyacceptable acid or base.
 21. A compound of formula (I) according toclaim 1 wherein A forms with the group to which it is bonded a1,2-dihydroacenaphthylene or7,8,9,10-tetrahydrocyclohepta[de]naphthalene tricyclic system, eachunsubstituted or substituted on the naphthalene moiety by one or twoalkoxy groups and substituted in the a or c position by ═CH—B,═CH—CH₂—B, —B, —CH₂—B or —(CH₂)₂—B wherein B represents NHCOR⁵ orCONHR⁶, their enantiomers and diastereoisomers, and addition saltsthereof with a pharmaceutically acceptable acid or base.
 22. A compoundof formula (I) according to claim 1 wherein A forms with the group towhich it is bonded a 2,3-dihydrophenalene tricyclic system,unsubstituted or substituted on the naphthalene moiety by one or twoalkoxy groups and substituted in the a or c position by ═CH—B,═CH—CH₂—B, —CH₂—B or —(CH₂)₂—B wherein B represents NHCOR⁵ or CONHR⁶,their enantiomers and diastereoisomers, and addition salts thereof witha pharmaceutically acceptable acid or base.
 23. Compounds of formula (I)according to claim 1 which are:N-[(4-methoxy-2,3-dihydro-1H-1-phenalenyl)methyl]acetamide,N-[(4-methoxy-2,3-dihydro-1H-phenalenyl)methyl]propionamide,N-[(4-methoxy-2,3-dihydro-1H-1-phenalenyl)methyl]-cyclopropanecarboxamide,N-[(4-methoxy-2,3-dihydro-1H-1-phenalenyl)methyl]-butanamide,N-[(4-methoxy-2,3-dihydro-1H-1-phenalenyl)methyl]butanamide,N-[2-(9-methoxy-2,3-dihydro-1H-1-phenalenyl)methyl]acetamide,N-[2-(9-methoxy-2,3-dihydro-1H-1-phenalenyl)methyl]butanamide,N-[2-(4,9-dimethoxy-2,3-dihydro-1H-1-phenalenyl)methyl]acetamide,N-[2-(4,9-dimethoxy-2,3-dihydro-1H-1-phenalenyl)-methyl]propanamide,N-[2-(4,9-dimethoxy-2,3-dihydro-1H-1-phenalenyl)methyl]-butanamide andN-[2-(4,9-dimethoxy-2,3-dihydro-1H-1-phenalenyl)methyl]-1-cyclopropanecarboxamide,their enantiomers and diastereoisomers, and addition salts thereof witha pharmaceutically acceptable acid or base.
 24. Compounds of formula (I)according to claim 1 which are:N-[2-(4-methoxy-2,3-dihydro-1H-1-phenalenyl)ethyl]acetamide,N-[2-(4-methoxy-2,3-dihydro-1H-1-phenalenyl)ethyl]propanamide,N-[2-(4-methoxy-2,3-dihydro-1H-1-phenalenyl)-ethyl]-1-cyclopropanecarboxamide,N-[2-(9-methoxy-2,3-dihydro-1H-1-phenalenyl)-ethyl]acetamide,N-[2-(9-methoxy-2,3-dihydro-1H-1-phenalenyl)ethyl]butanamide,N-[2-(4-methoxy-2,3-dihydro-1H-1-phenalenyl)ethyl]butanamide,N-[2-(4,9-di-methoxy-2,3-dihydro-1H-1-phenalenyl)ethyl]propanamide,N-[2-(4,9-dimethoxy-2,3-dihydro-1H-1-phenalenyl)ethyl]butanamide,N-[2-(4,9-dimethoxy-2,3-dihydro-1H-1-phenalenyl)ethyl]-1-cyclopropanecarboxamideand N-[2-(4,9-dimethoxy-2,3-dihydro-1H-1-phenalenyl)ethyl]acetamide,their enantiomers and diastereoisomers, and addition salts thereof witha pharmaceutically acceptable acid or base.
 25. Compound of formula (I)according to claim 1 which isN-(8-methoxy-1,2-dihydro-1-acenaphthylenyl)acetamide, its enantiomersand diastereoisomers, and addition salts thereof with a pharmaceuticallyacceptable acid or base.
 26. Compounds of formula (I) according to claim1 which are:(E)-N-methyl-2-(4-methoxy-2,3-dihydro-1H-1-phenalenylidene)acetamide and(Z)-N-methyl-2-(4-methoxy-2,3-dihydro-1H-1-phenalenylidene)acetamide,their enantiomers and diastereoisomers, and addition salts thereof witha pharmaceutically acceptable acid or base.
 27. Compounds of formula (I)according to claim 1 which are:N-(1,2-dihydro-1-acenaphthylenylmethyl)acetamide,N-(1,2-dihydro-1-acenaphthylenylmethyl)propanamide,N-(1,2-dihydro-1-acenaphthylenylmethyl)butanamide,N-(1,2-dihydro-1-acenaphthylenylmethyl)-1-cyclopropanecarboxamide,N-(8-methoxy-1,2-dihydro-1-acenaphthylmethyl)acetamide,N-(8-methoxy-1,2-dihydro-1-acenaphthylmethyl)-propanamide,N-(8-methoxy-1,2-dihydro-1-acenaphthylmethyl)-1-cyclopropanecarboxamideand N-(8-methoxy-1,2-dihydro-1-acenaphthylmethyl)butanamide, theirenantiomers and diastereoisomers, and addition salts thereof with apharmaceutically acceptable acid or base.
 28. Compounds of formula (I)according to claim 1 which are:N-[2-(1,2-dihydro-1-acenaphthyl)ethyl]acetamide,N-[2-(1,2-dihydro-1-acenaphthyl)ethyl]propanamide,N-[2-(1,2-dihydro-1-acenaphthyl)ethyl]butanamide,N-[2-(1,2-dihydro-1-acenaphthyl)ethyl]cyclopropanecarboxamide,N-[2-(8-methoxy-1,2-dihydro-1-acenaphthyl)ethyl]acetamide,N-[2-(8-methoxy-1,2-dihydro-1-acenaphthyl)ethyl]propanamide,N-[2-(8-methoxy-1,2-dihydro-1-acenaphthyl)ethyl]butanamide andN-[2-(8-methoxy-1,2-dihydro-1-acenaphthyl)ethyl]-1-cyclopropanecarboxamide,their enantiomers and diastereoisomers, and addition salts thereof witha pharmaceutically acceptable acid or base.
 29. A compound of formula(I) according to claim 1 which isN-[2-(1-methoxy-7,8,9,10-tetrahydrocyclohepta[de]naphthalen-7-ylidene)ethyl]propanamide,its enantiomers and diastereoisomers, and addition salts thereof with apharmaceutically acceptable acid or base.
 30. A method for treating aliving body afflicted with disorders of the melatoninergic systemcomprising the step of administering to the living body an amount of acompound of claims 1 to 29 which is effective for the alleviation forsaid condition.
 31. A pharmaceutical composition useful for treatingmelatoninergic disorders comprising, as active principle an effectiveamount of a compound as claimed in claims 1 to 29, together with one ormore pharmaceutically acceptable excipients or vehicles.